CHAPTER 81
Inherited Metabolic Diseases

Andrew Morris

Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

Introduction

Inherited metabolic diseases or ‘inborn errors of metabolism’ are caused by deficiencies of enzymes or transport proteins. They are extremely diverse and often affect several different systems of the body. They are generally classified according to the organelle or pathway involved. Inherited metabolic diseases with dermatological features are listed in Table 81.1, which also indicates whether the disorder is considered here or elsewhere in this textbook.

Table 81.1 Inherited metabolic diseases with dermatological features.

Disorder	Example	Where considered
Lysosomal disorders	Fabry disease, MPS, etc.	This chapter
Mitochondrial disorders		This chapter
Peroxisomal disorders	Refsum disease	Chapter 65
Congenital defects of glycosylation	Phosphomannomutase 2 deficiency	This chapter
	ATP6VOA2 defects	Chapter 96
Amino acid disorders	Phenylketonuria	This chapter
	Tyrosinaemia	This chapter and Chapter 65
	Prolidase deficiency	This chapter
	Alkaptonuria, Hartnup disease, etc.	This chapter
Carbohydrate disorders	Glycogen storage disease type I	Chapter 62
Lipid disorders	Hyperlipidaemias	Chapter 62
	Cerebrotendinous xanthomatosis	Chapter 62
	Smith–Lemli–Opitz syndrome and mevalonic aciduria	This chapter
	Conradi–Hünermann syndrome	Chapter 65
	Sjögren–Larsson syndrome	Chapter 65
	Neutral lipid storage disorder (Chanarin–Dorfman)	Chapter 65
	Steroid sulphatase deficiency	Chapter 65
Nucleic acid disorders	Lesch–Nyhan syndrome	This chapter
Haem disorders	Porphyrias	Chapter 60
Vitamin disorders	Biotinidase and holocarboxylase synthetase deficiencies	This chapter and Chapter 68
Mineral disorders	Acrodermatitis enteropathica	This chapter
	Menkes disease and occipital horn syndrome	This chapter and Chapter 96
	Wilson disease	This chapter
	Haemochromatosis	Chapter 88

Lysosomes are a major site for the degradation of macromolecules and contain more than 50 acid hydrolases. Lysosomal storage disorders are inherited conditions in which deficiency of one or more hydrolases leads to the accumulation of various molecules in lysosomes. Typically, these are progressive multisystem diseases but the clinical features vary depending on the precise disorder and the severity of the enzyme deficiency. The characteristic dermatological findings are angiokeratomas (most commonly seen in Fabry disease) and thickened skin and hypertrichosis, which lead to a ‘coarse’ facial appearance when combined with abnormalities of the facial skeleton (as in the mucopolysaccharidoses).

Mucopolysaccharidoses

Introduction and general description

The mucopolysaccharidoses (MPSs) are a family of inherited multisystem disorders caused by defects in the degradation of glycosaminoglycans, which accumulate within lysosomes. Clinical features include a ‘coarse’ facial appearance, hepatosplenomegaly, bone dysplasia and developmental regression. Some of these features are absent in some disorders. Moreover, there is a considerable range of severity for each disorder: for MPS I, the spectrum is divided into Hurler syndrome (severe), Hurler–Scheie (intermediate) and Scheie syndrome (relatively mild). MPS III can result from deficiencies of four different enzymes. The biochemical and clinical features of the different disorders are summarized in Table 81.2, along with the synonyms and MIM classification links.

Table 81.2 Classification of the mucopolysaccharidoses (MPSs).

Number^a	MIM no.	Eponym	Clinical features	Enzyme deficiency	GAGs stored and excreted
MPS IH	252800	Hurler	Dysmorphism, corneal clouding, DM, HSM, PR, heart disease, death in childhood	α-L-iduronidase	DS, HS
MPS IS	252800	Scheie	Dysmorphism, corneal clouding, DM, normal IQ and lifespan	α-L-iduronidase	DS, HS
MPS IH/S	252800	Hurler–Scheie	Phenotype intermediate between IH and IS	α-L-iduronidase	DS, HS
MPS II	309900	Hunter (severe)	Dysmorphism, DM, HSM, heart disease, PR, death before 15 years	Iduronate sulphatase	DS, HS
		Hunter (mild)	Normal IQ, short stature, survive to adulthood	Iduronate sulphatase	DS, HS
MPS IIIA	252900	Sanfilippo A	PR, regression, hyperactivity, mild somatic features	Heparan-N-sulphatase	HS
MPS IIIB	252920	Sanfilippo B	Similar to IIIA	α-N-acetyl-glucosaminidase	HS
MPS IIIC	252930	Sanfilippo C	Similar to IIIA	Acetyl-CoA glucosamine-N-acetyl-transferase	HS
MPS IIID	252940	Sanfilippo D	Similar to IIIA	N-acetyl-glucosamine 6-sulphatase	HS
MPS IVA	253000	Morquio A	DM, odontoid hypoplasia, corneal clouding	Galactose 6-sulphatase	KS
MPS IVB	253010	Morquio B	Milder DM, slow neurodegeneration	ß-galactosidase	KS
MPS VI	253200	Maroteaux–Lamy	Dysmorphism, DM, corneal clouding, normal IQ	N-acetyl-galactosamine 4-sulphatase	DS
MPS VII	253220	Sly	Hydrops fetalis, dysmorphism, DM, HSM, PR	ß-glucoronidase	DS, HS
MPS IX	601492	Natowicz	Soft tissue masses in the one reported patient	Hyaluronidase	Hyaluronan

^aThe terms MPS V and MPS VIII are no longer used.

DM, dysostosis multiplex; DS, dermatan sulphate; GAG, glycosaminoglycan; HS, heparan sulphate; HSM, hepatosplenomegaly; IQ, intelligence quotient; KS, keratan sulphate; PR, psychomotor retardation.

Incidence

The total incidence of MPS is approximately 1 : 25 000.

Pathophysiology

Glycosaminoglycans (GAGs, formerly known as mucopolysaccharides) are long sugar chains composed of alternating sulphated hexuronic acid and hexosamine residues; in connective tissue, they are bound to core proteins to form proteoglycans. Dermatan sulphate, heparan sulphate and keratan sulphate are the main GAGs that accumulate in the MPS disorders.

Genetics

All the MPSs are inherited as autosomal recessive traits except for MPS II (Hunter syndrome), which is X-linked.

Clinical features

Presentation

Mucopolysaccharidosis patients usually present in early childhood with developmental delay, deafness and upper airway problems; a few patients present with skeletal or cardiac problems.

Dysmorphism.

MPS patients often have a ‘coarse’ facial appearance (Figure 81.1). The term ‘coarse’ should be avoided when talking to families, as many find it offensive. The dysmorphism is seldom noticeable at birth and becomes more apparent with time. Hypoplasia of the mid-facial bones leads to a flat nasal bridge. The skin is thickened, as are the lips, and the tongue is enlarged. The mouth is often slightly open due to adenoidal hypertrophy and the need for mouth breathing. Many patients have generalized hypertrichosis and some have synophrys. Corneal clouding is seen in MPS I, VI and VII. The hands appear podgy with short, broad digits. The facial dysmorphism is absent in MPS IV and relatively subtle in MPS III.

Image described by caption. — **Figure 81.1** Facial features of an 8-year-old boy with Hunter syndrome (MPS II).

Other dermatological features.

Ivory white papules or nodules are often seen on the back of patients with severe MPS II (Hunter syndrome); similar pebbly skin may also occur in MPS I (Hurler and Hurler–Scheie syndromes). Individual nodules range from 1 to 10 mm in size and they may coalesce to form ridges or a reticular pattern [1]. Typically, they are found laterally, between the angles of the scapulae and posterior axillary lines (Figure 81.2). Papules may also be found on the upper arms and outer thighs. Typically, the papules appear at 1–4 years of age and progress for a few years; they may clear spontaneously in older patients. Mongolian blue spots are common in Hurler and Hunter syndromes and, in addition to the sacro-coccygeal region, they may be found on the upper back, the anterior trunk or the limbs. The spots fade more slowly than in the general population: in Japanese patients they persist until the teenage years [2].

Developmental regression.

This is the dominant feature in MPS III (Sanfilippo syndrome). After a period of hyperactivity, behaviour problems and sleep disturbance, patients gradually deteriorate into a vegetative state. Learning difficulties are also present in Hurler syndrome and severe cases of MPS II and VII. Other neurological problems may include seizures, hydrocephalus, spinal cord compression and carpal tunnel syndrome.

Bone dysplasia.

This is known as dysostosis multiplex and is a particular problem in patients with MPS IV (Morquio disease). These patients have very short stature and joint laxity leading to arthritis of the hip and knee and a risk of atlanto-axial dislocation. In the other MPSs, the joints are stiff and short stature is associated with kyphosis.

Other features.

Ear, nose and throat infections, upper airway obstruction and deafness are common. Valvular heart disease is often the cause of death.

Differential diagnosis

Mucopolysaccharidosis-like problems (including coarse facial features) occur in other lysosomal disorders, such as glycoprotein breakdown disorders, mucolipidoses and a few sphingolipidoses (the severe forms of galactosialidosis and G_M1 gangliosidosis). Patients presenting with an MPS-like phenotype at birth are likely to have mucolipidosis type II or G_M1 gangliosidosis. The differential diagnoses can be identified by analysis of urinary oligosaccharides, combined with lysosomal enzyme assays in plasma and leukocytes.

Investigations

The most valuable investigation is analysis of urine GAGs, preferably by two-dimensional electrophoresis. The diagnosis can be confirmed by enzyme assay in leukocytes, plasma or fibroblasts; mutation analysis is also possible.

Histology

The skin may show distinctive changes even in the absence of clinical skin abnormalities. Malpighian cells in the epidermis are distended with pale cytoplasm. Fibroblasts, Schwann cells and some smooth muscle and sweat gland cells show cytoplasmic metachromasia when stained with toluidine blue (due to the presence of GAGs). Fragmentation of collagen and increased tissue mucin may be seen. The papules in Hunter syndrome show pooling of metachromatic material between the collagen bundles of the lower reticular dermis. Ultrastructurally, in all forms of MPS, dermal fibroblasts and Schwann cells contain membrane-bound cytoplasmic vacuoles, which may appear empty or contain fibrillogranular material [3].

Management

Symptomatic treatment is important. Ear, nose and throat, orthopaedic and neurosurgery involvement may all be needed. Medication can be useful for sleep and behaviour problems, especially in MPS III. Haematopoietic stem cell transplantation (HSCT) is an established treatment for Hurler and Maroteaux–Lamy syndromes, using bone marrow or umbilical cord blood [4]. Transplantation in infancy leads to an improvement in most systems and can preserve normal developmental progress in Hurler syndrome but the skeletal problems progress and ophthalmological problems persist. Moreover, HSCT has significant morbidity and mortality. Enzyme replacement therapy is now available for MPS I, II, IV and VI. Its major limitation is the inability of the enzyme to cross the blood–brain barrier. Bone and heart valve disease are also resistant to enzyme replacement therapy, although outcomes can be improved by starting treatment early [5].

Glycoprotein degradation disorders

Most secreted and cell surface proteins are glycosylated. The oligosaccharide components of glycoproteins are degraded by lysosomal hydrolases. Deficiency of an enzyme leads to the storage of various oligosaccharides and/or glycopeptides, depending on the precise defect. The disorders are all very rare. Some resemble the mucopolysaccharidoses with, for example, a similar facial appearance and skeletal dysplasia (known as dysostosis multiplex). Angiokeratomas occur in some disorders. The clinical and biochemical features are summarized in Table 81.3. Details of individual disorders are given below.

Table 81.3 Glycoprotein storage disorders, sphingolipidoses and mucolipidoses with cutaneous features.

Name	Enzyme deficiency	Cutaneous features^a	Other clinical features^b	Abnormal urine oligosaccharides	Sample for enzymology
Glycoprotein degradation disorders
Fucosidosis	α-l-fucosidase	MLF (mild), AK	PR	(+)	Leukocytes
α-Mannosidosis	α-mannosidase	MLF	PR, deafness, DM, HSM, frequent infections	+	Leukocytes
β-Mannosidosis	β-mannosidase	AK	PR, deafness, frequent infections	(+)	Leukocytes
Sialidosis type II	neuraminidase	MLF	PR, DM, HSM	(+)	Cultured cells
Aspartylglucosaminuria	Aspartylglucosaminidase	MLF, AK	PR, regression, seizures	(+)	Leukocytes
Kanzaki	α-N-acetylgalactosaminidase	AK, MLF (mild)	PR
Sphingolipidoses
Fabry	α-galactosidase A	AK, hypohydrosis	Acroparaesthesia, renal failure, heart disease, strokes		Leukocytes
G_M1 gangliosidosis (early-onset form)	β-galactosidase	MLF, AK, T	Hydrops, HSM, DM, PR, regression, spasticity, CRS	+	Leukocytes
Galactosialidosis (early-onset form)	PPCA	MLF, T	Hydrops, HSM, heart disease, DM, PR, CRS	+	Leukocytes
Galactosialidosis (later-onset form)	PPCA	AK, MLF (mild)	Myoclonus, ataxia, PR, CRS	+	Leukocytes
Gaucher types I and III	β-glucosidase	Pigmentation, T	Bone pain, DM, HSM ± regression (type III)		Leukocytes
Gaucher type II	β-glucosidase	Collodion baby	HSM, squint, stridor, dysphagia, spasticity		Leukocytes
Niemann–Pick A	Sphingomyelinase	Papules, pigmentation	HSM, lymphadenopathy, PR, regression, spasticity, CRS		Leukocytes
Niemann–Pick B	Aphingomyelinase	Papules, pigmentation	HSM, lung disease		Leukocytes
Farber	Ceramidase	Nodules	Hoarse voice, arthritis, PR, regression, CRS		Leukocytes
Mucolipidoses and other disorders
Mucolipidosis type II	Multiple	MLF	Gum hypertrophy, DM, PR, cardiomyopathy	+	Plasma
Mucolipidosis type III	Multiple	MLF (mild)	Arthritis, DM, PR	+	Plasma
Multiple sulphatase deficiency	Multiple	MLF ± ichthyosis	PR, regression, HSM, DM	+	Leukocytes
ISSD	Sialic acid transporter	MLF, hypopigmentation	PR, HSM, DM, hydrops/ascites	+	Cultured cells

^aFeatures that are characteristic or have been reported in a number of patients.

AK, angiokeratomas; CRS, cherry red spot; DM, dysostosis multiplex; HSM, hepatosplenomegaly; ISSD, infantile free sialic acid storage disease; MLF, mucopolysaccharidosis-like facies; PPCA, protective protein/cathepsin A; PR, psychomotor retardation; T, telangiectasia.

Pathophysiology

Genetics

All disorders of glycoprotein degradation are inherited as autosomal recessive traits.

Investigations

Abnormal oligosacharides can be detected in the urine by thin-layer chromatography in α-mannosidosis, sialidosis and aspartylglucosaminuria but they are not consistently present in ß-mannosidosis or fucosidosis. Enzyme assays are, therefore, crucial in establishing these diagnoses. Most of the enzyme assays can be performed on leukocytes but neuraminidase can only be measured reliably in cultured cells. Many laboratories offer a set of lysosomal enzyme assays on leukocytes for screening patients with relevant clinical features. Electron microscopy of the skin often shows cytoplasmic vacuoles, particularly in endothelial cells, fibroblasts, Schwann cells and the myoepithelial cells of sweat glands [6, 7].

Management

For most of these disorders, only symptomatic treatment is available. Enzyme replacement therapy is being developed for α-mannosidosis and bone marrow transplantation may improve the neurological outcome in fucosidosis.

Individual glycoprotein degradation disorders

Fucosidosis.

Fucosidosis (MIM: 230000) presents in early childhood with developmental delay, followed by neurological deterioration. Other clinical features include a mild MPS-like facial appearance, short stature, hypohydrosis and hepatosplenomegaly. Angiokeratomas appear in mid to late childhood and are present in 85% of patients aged over 20 years [8]. The angiokeratomas usually have the same appearance and distribution as in Fabry disease but in some patients they are confined to the limbs (Figure 81.3). Similar lesions may occur on the lips, gums or tongue.

Alpha-mannosidosis.

α-mannosidosis (MIM: 248500) is associated with MPS-like facial features, learning difficulties, deafness, corneal clouding and cataracts, dysostosis multiplex, hepatosplenomegaly and frequent infections.

Beta-mannosidosis.

β-mannosidosis (MIM: 248510) presents with learning difficulties, deafness and frequent infections; the face is not coarse but angiokeratomas are occasionally present.

Sialidosis.

Sialidosis (MIM: 256550) occurs in two main types. Mildly affected patients are said to have sialidosis type I: they present as adolescents or adults with myoclonus, visual impairment and a macular ‘cherry red spot’ on fundoscopy. Sialidosis type II patients present in early childhood with an MPS-like apprearance, developmental delay, dysostosis multiplex and hepatosplenomegaly.

Aspartylglucosaminuria.

Aspartylglucosaminuria (MIM: 208400) is extremely rare except in Finland. Patients have developmental delay in childhood and regress after puberty, eventually becoming severely retarded. There is gradual coarsening of the facial features, with sagging skin, thick lips, a broad low nasal bridge and coarse hair. Facial angiofibromas are common in adults, as are gingival overgrowths and oedema of the buccal mucosa [9]. Angiokeratomas are less common and may be confined to the limbs.

Alpha-N-acetyl-galactosaminidase deficiency.

α-N-acetyl-galactosaminidase deficiency (MIM: 104170) is extremely rare. It has been reported in infants with neurodegeneration (Schindler disease) and in adults with angiokeratomas and mild learning difficulties (Kanzaki disease). The angiokeratomas may have a similar distribution to Fabry disease, or they may be more widespread, including across the breasts, extremities, face, lips, mouth and gastric mucosa [6].

Mucolipidoses types II and III

Introduction and general description

These are autosomal recessive disorders, in which multiple lysosomal enzymes fail to enter their organelle. Mucolipidosis (ML) II (or I cell disease) refers to the severe end of the spectrum: patients often present at birth with coarse facial features. They also have gum hypertrophy, severe neurological involvement, dysostosis multiplex and cardiomyopathy. In ML III, the main problem is arthritis (due to skeletal dysplasia); there may also be mild learning difficulties (see Table 81.3).

Investigations

The diagnosis is established by demonstrating raised levels of the mis-targeted lysosomal enzymes in plasma. Cultured fibroblasts from patients with ML II and III contain dense cytoplasmic inclusions, which gave rise to the name, I cell disease. Skin histology reveals membrane-bound vacuoles and cytoplasmic bodies in fibroblasts and other mesenchymal cells.

Management

Only symptomatic treatment is available.

Sphingolipidoses

Introduction and general description

Sphingolipids are amphiphilic molecules found in cell membranes. They are degraded by lysosomal hydrolases and deficiencies of these enzymes (or their protector proteins) cause the sphingolipidoses. In some sphingolipidoses (e.g. Tay–Sachs disease), problems are confined to the nervous system: these are not considered further here. Other sphingolipidoses may be associated with an MPS-like facial appearance, angiokeratomas or other dermatological abnormalities. The clinical and biochemical features of sphingolipidoses with dermatological features are included in Table 81.3. Because of its importance, Fabry disease is described separately.

Pathophysiology

Genetics

All the sphingolipidoses are autosomal recessive disorders, except Fabry disease, which is X-linked.

Clinical features

G_M1 gangliosidosis.

G_M1 gangliosidosis (MIM: 230500) is very rare and has a wide clinical spectrum. Severe cases present as neonates with hydrops fetalis or hypotonia, hepatosplenomegaly and facial dysmorphism (including macroglossia, gum hypertrophy and a depressed nasal bridge). Neurodegeneration is the main feature in other cases. The mildest cases present in late childhood with dysarthria, dystonia and skeletal dysplasia (affecting the spine and hip). Angiokeratomas are prominent in a few patients with infantile G_M1 gangliosidosis, affecting the trunk, thighs and upper arms [10]. Telangiectasia and extensive Mongolian blue spots have also been reported in infantile cases.

Galactosialidosis.

Galactosialidosis (MIM: 256540) is extremely rare. Deficiency of a protective protein (protective protein/cathepsin A, PPCA) leads to a combined deficiency of neuraminidase and ß-galactosidase. Neonatal-onset patients resemble those with G_M1 gangliosidosis and often have telangiectasia. Later-onset cases have mild MPS-like facial features and neurodegeneration; angiokeratomas are commoner in these patients [11].

Gaucher disease.

Gaucher disease (MIM: 606463) is the most prevalent lysosomal disorder (1 : 50 000). It is classified clinically into three types, of which type I (non-neuronopathic) is much the commonest [12]. This presents in children or adults with hepatosplenomegaly, thrombocytopenia (due to hypersplenism) or bone problems (ischaemic crises, bone pain or pathological fractures). Type II (acute neuronopathic) patients present by 6 months of age with neurological problems (squint, dysphagia and opisthotonus), poor weight gain and hepatosplenomegaly; most die by 2 years. Type III disease (subacute neuronopathic) presents in young children with hepatosplenomegaly, followed by an eye movement disorder and other neurological problems.

Cutaneous features are common in type I but not troublesome and include diffuse yellow-brown pigmentation, easy tanning, brown macules and telangiectasia [13]. Thrombocytopenia may lead to petechiae or ecchymoses. A few type II patients have congenital ichthyosis leading to the collodion baby phenotype (Figure 81.4). The baby is encased in thick, tight, shiny skin that cracks and desquamates to leave erythroderma [14]. There is ectropia of the eyes. The skin may return to normal if the baby survives for more than a month.

Niemann–Pick disease.

Niemann–Pick disease (MIM: 257200) due to sphingomyelinase deficiency is classified into type A (neuronopathic) and type B (non-neuronopathic); type C is an unrelated disorder of intracellular lipid trafficking and is not considered here. Type A usually presents in early infancy with diarrhoea and vomiting, poor weight gain, hepatosplenomegaly and neurological problems; these patients die by 3 years of age. Less severely affected type A patients have juvenile- or adult-onset neurological disease. Type B patients present as children or adults with splenomegaly or hepatosplenomegaly; complications include interstitial lung disease, poor growth, hyperlipidaemia and thrombocytopenia.

The skin may be involved in types A or B, with patches of waxy induration and brownish yellow pigmentation. Papular, papulonodular or suppurative lesions may be found on the face or trunk, occasionally becoming confluent [15, 16]. Histology shows foamy macrophages. Mongolian blue spots occur in children.

Farber disease.

Farber disease (MIM: 228000) is extremely rare. Patients usually present in early infancy with a hoarse cry, painful swollen joints and subcutaneous nodules. The most commonly affected joints are those of the hand and wrist, elbows, knees and ankles. The subcutaneous nodules may be associated with erythematous papules and are generally close to affected joints and over pressure points, such as the occiput and lower spine. Histology reveals granulomas containing large, foamy histiocytes; electron microscopy shows that these have cytoplasmic vacuoles containing curvilinear inclusions (Farber bodies) [17]. Most patients have psychomotor retardation, poor weight gain and die in early childhood from respiratory infections.

Investigations

The diagnosis is established by enzyme assays on leukocytes (or cultured cells).

Histology

‘Foam cells’ are found in the bone marrow and, to a lesser extent, in the skin. Niemann–Pick cells are typical examples – large, usually mononucleate histiocytes, whose cytoplasm is filled with lipid droplets; they stain readily with Sudan stains and contain doubly refractile material. Ultrastructurally, the cytoplasm of Niemann–Pick cells contains granular lipid inclusions that may appear lamellar [15]. Gaucher cells differ markedly from the foam cells seen in other lipidoses. They are large cells with pale-staining cytoplasm that has a delicate, striated, ‘wrinkled tissue paper’ appearance. Ultrastructurally, Gaucher cells have vesicles that contain twisted tubular structures [18].

Management

Enzyme replacement therapy is available for Fabry disease and Gaucher disease type 1 but it is expensive and requires slow intravenous infusion at least every 2 weeks [12]. In the UK, ERT is given to paediatric patients with Gaucher disease type 1 and to adults with significant symptoms. ERT relieves the systemic complications in Gaucher disease type 3 but HSCT should be considered if there is neurological deterioration. Miglustat is an oral drug that decreases the accumulation of glucocerebroside by reducing the synthesis of glycosphingolipids (substrate reduction therapy) [12]. In the UK, it is licensed in Niemann–Pick disease type C and in patients with Gaucher disease type 1 who are unable to receive ERT. Diarrhoea and weight loss are common side effects. Only symptomatic treatment is available for other sphingolipidoses but ERT is being developed for Niemann–Pick disease type B.

Fabry disease

Introduction and general description

This is a rare X-linked lysosomal storage disorder, characterized by angiokeratomas and multisystem complications [19]. Affected males usually present in childhood with episodes of pain in the extremities, followed by the appearance of angiokeratomas. Most adult males develop renal failure, cardiac and cerebrovascular disease. Many heterozygous females also develop symptoms, although the onset is usually later.

Incidence

There is an incidence of one in 40 000–60 000 male births.

Pathophysiology

A deficiency of α-galactosidase A prevents the degradation of glycosphingolipids with terminal galactose residues, predominantly globotriaosylceramide (Gb3). Gb3 accumulation in vascular endothelial, perithelial and smooth muscle cells leads to aneurysmal dilatation of blood vessels, ischaemia and infarction. Glycosphingolipids also accumulate in the renal glomeruli and tubules, cardiac muscle, autonomic ganglion cells and corneal epithelium.

Genetics

Fabry disease shows X-linked recessive inheritance. More than 500 mutations have been identified in GLA, the gene for α-galactosidase A; none are highly prevalent. The p.N215S mutation is associated with the mild ‘cardiac’ variant [20].

Clinical features

The first symptoms are usually episodes of severe burning pain in the palms and soles (acroparesthesiae). These occur in 70–85% of male patients, usually starting at between 5 and 15 years of age, although diagnosis is often delayed [21]. Acroparesthesiae occur in 50–70% of female patients, with a mean age of onset of 15 years [22]. Painful crises are often triggered by fever or exertion and may last hours or days. Pain may diminish spontaneously in older men.

Angiokeratoma corporis diffusum occurs in 65–70% of male patients and 35–40% of female patients [21, 22]. In males, angiokeratomas often start to appear shortly before puberty (age of onset 19 ± 14 years, mean ± SD) whereas in females they usually appear later (28 ± 17 years). The initial lesion is a dark red or black telangiectatic macule or papule, up to 4 mm across, that does not blanch with pressure; there is usually mild hyperkeratosis over larger lesions. Angiokeratomas are clustered and may be numerous or sparse. In men, the commonest sites are around the umbilicus (Figure 81.5) and in the bathing trunk area: inner thighs, lower back, buttocks, penis and scrotum. Lesions may also be found on the upper arms, around the border of the lips, around the nail folds and on the palms and soles – these are usually macular angiomas with minimal hyperkeratosis. In women, lesions are most frequent on the trunk and proximal limbs; genital lesions are rare. Telangiectases are present in 23% of male patients and 9% of female patients, usually on the lips, buccal mucosa, ears or conjunctiva [23].

Anhidrosis or hypohidrosis occurs in 53% of male patients and 28% of female patients, usually starting in the third decade [23]. It probably results from autonomic neuropathy and is associated with heat and exercise intolerance. Hyperhidrosis occurs in 10% of patients, predominantly females, often starting in adolescence. Later, vasomotor disturbances may cause flushing, cyanosis or blanching of the hands. Lymphoedema is common and may be due to lymphatic microangiopathy [23].

Clinical variants

Men with the ‘cardiac variant’ usually present after the age of 40 years with cardiomyopathy and proteinuria.

Differential diagnosis

The differential diagnosis for angiokeratomas includes purpura, angioma serpiginosum and other causes of angiokeratomas. Localized types of angiokeratoma include circumscriptum, scrotal (Fordyce type) and Mibelli type. Angiokeratoma corporis diffusum occurs in several other lysosomal disorders, although Fabry disease is much the commonest cause (Table 81.4). There have been a few reports of patients with angiokeratoma corporis diffusum in whom no specific enzyme deficiency has been identified.

Table 81.4 Lysosomal diseases associated with angiokeratomas.

Name/eponym	Enzyme deficiency	Usual age of onset	Ultrastructure of lysosomal storage in mesenchymal cells
Fabry	α-galactosidase A	>10 years (males), adulthood (females)	Dense concentric lamellar inclusions
Fucosidosis	α-L-fucosidase	Mid to late childhood	Vacuoles with granular material
Kanzaki	α-N-acetylgalactosaminidase	Adulthood	Vacuoles with fibrillary material
Galactosialidosis	β-galactosidase and neuraminidase	Adulthood	Vacuoles with granular material
G_M1 gangliosidosis	β-galactosidase	Infancy	Vacuoles with fibrillogranular material
Aspartylglycosaminuria	Aspartylglucosaminidase	Late childhood or adulthood	Vacuoles with fibrillogranular material
β-Mannosidosis	β-mannosidase	Late childhood or adulthood	Vacuoles with granular material

Complications and co-morbidities

Cardiac involvement occurs in almost all adult males with Fabry disease. It includes left ventricular dilatation and hypertrophy, mitral valve regurgitation, arrhythmias and ischaemic heart disease. Most men have proteinuria, hypertension and gradually deteriorating renal function. Without enzyme replacement therapy, end-stage renal failure is usually reached between 40 and 50 years of age [21]. Cerebrovascular disease leads to early strokes or transient ischaemic attacks. Some patients develop neurological problems without obvious thrombotic episodes, presumably due to the involvement of multiple small vessels. Cardiac and cerebrovascular disease are commoner in heterozygous women than previously thought: in a survey of 248 women, 7% had suffered strokes at a mean age of 50 years [24]. Vertigo, dizziness and hearing loss are common. Other complications include abdominal pain and diarrhoea, achalasia of the oesophagus and arthritis in the fingers.

Prognosis

Life expectancy is reduced with a median survival of 50 years in male patients and 70 years in heterozygous females.

Investigations

The diagnosis of Fabry disease can be established by skin histology or slit lamp examination of the cornea. In males, the diagnosis should be confirmed by demonstrating α-galactosidase A deficiency in plasma, leukocytes or cultured skin fibroblasts. In women, the diagnosis is confirmed by molecular analysis because enzyme activity is often normal.

Histology

Light microscopy of the angiokeratomas shows dilated vessels in the upper dermis beneath a thinned epidermis, with or without hyperkeratosis (Figure 81.6). The diagnostic feature is the presence of vacuolated cells in the media and intima of small blood vessels. The accumulating glycosphingolipids are birefringent and, in frozen sections, they appear as ‘Maltese crosses’ in polarized light. Electron microscopy shows cytoplasmic inclusion bodies in the endothelial (Figure 81.7) and perithelial cells of blood vessels, smooth muscle, perineural cells and dermal macrophages. The inclusions are present in clinically unaffected skin, even in infancy; they are electron dense and lamellar, with a periodicity of 4–6 nm [25]. In contrast, other lysosomal disorders associated with angiokeratomas have electron-lucent vacuoles containing scanty fibrillary or granular material.

Slit lamp examination of the eye

Most adult patients (male and female) have an asymptomatic corneal dystrophy. Initial haziness progresses to characteristic whorled streaks radiating to the periphery (cornea verticillata). Identical appearances can result from long-term treatment with chloroquine or amiodarone. Other findings include lens opacities and tortuosity of the conjunctival and retinal vessels.

Management

The acroparesthesiae may respond to carbamazepine, gabapentin or phenytoin or they may require opiates. Angiokeratomas can be removed by laser therapy for cosmetic or other reasons but this is seldom requested. Cardiac complications should be managed conventionally. Aspirin may reduce the risk of stroke and angiotensin-converting enzyme inhibitors should be started if there is proteinuria. Renal failure is treated with dialysis or transplantation: glycolipids do not reaccumulate in the graft. Enzyme replacement therapy (ERT) reduces neurogenic pain and left ventricular hypertrophy and prevents renal impairment in patients with normal baseline renal function [19]. In the UK, ERT is now started following diagnosis in symptomatic male patients; in female patients, it is started if there is cardiac, neurological or renal disease, troublesome gastrointestinal symptoms or pain that cannot be controlled by other means.

MITOCHONDRIAL RESPIRATORY CHAIN DISORDERS

The mitochondrial respiratory chain is responsible for the production of adenosine triphosphate (ATP) using energy released during the oxidation of cellular fuels. Due to the ubiquitous need for energy, mitochondrial disorders can affect any tissue; neuromuscular problems are commonest but, as the disease progresses, it often involves an increasing number of apparently unrelated organs. Multisystem presentations are particularly common in childhood but mitochondrial disorders can present at any age.

Mitochondrial disorders have unusually varied patterns of inheritance. Though most mitochondrial proteins are encoded by nuclear genes, mitochondria also have their own genome (mtDNA), which is inherited exclusively from the mother and there are hundreds of copies in each cell. These mtDNA mutations can be homoplasmic, when they affect all the copies in a cell, or heteroplasmic, when they only affect a proportion of the copies. For heteroplasmic mutations, the level of mutant mtDNA can vary within a maternal pedigree and clinical problems only occur when the level exceeds a threshold. Symptoms are usually more severe if the level of mutant mtDNA is very high than if it is just above the threshold.

Dermatological features of mitochondrial disorders

Multiple symmetrical lipomatosis

Lipomas are seen in adults with certain mtDNA mutations. Typically, there are multiple lipomas symmetrically distributed over the back of the neck and shoulders; they often recur following removal [26]. They are most frequently associated with the mtDNA mutations m.8344A>G and m.8363G>A, both of which affect the gene for mitochondrial tRNA^Lys [27]. Patients with these mutations at a high level of heteroplasmy often have neurological problems – the classic combination of myoclonus epilepsy and myopathy with ragged red fibres is given the acronym MERRF syndrome (MIM: 545000); other patients may have deafness, ataxia or a childhood neurodegenerative disorder called Leigh syndrome. Lipomas occur in patients with neurological problems and also in subjects with a lower level of the mutation who are otherwise asymptomatic. Within a single patient, the level of the mutation varies from one tissue to another and it is higher in the lipomas than in other tissues (such as unaffected adipose tissue). Cells within the lipomas are derived from brown fat [26] and have altered expression of genes involved in regulating adipogenesis [27].

Acrocyanosis

Orthostatic acrocyanosis is a characteristic finding in patients with ethylmalonic encephalopathy (MIM: 602473) [28]. Patients have intermittent red or purple discoloration of the feet (± hands) without trophic changes. They may also have a recurrent petechial rash and bruising (with normal platelets and clotting studies). Other problems include chronic diarrhoea, poor growth, developmental delay and regression, seizures and episodes of coma. Most patients present in infancy and die in early childhood, although some follow a less severe course. Ethylmalonic encephalopathy is an autosomal recessive disorder caused by mutations in ETHE1, a mitochondrial sulphur dioxygenase. Deficiency of this enzyme leads to the accumulation of hydrogen sulphide, which is vasoactive and damages small blood vessels, accounting for the acrocyanosis and petechiae [29]. Hydrogen sulphide also inhibits cytochrome oxidase (leading to mitochondrial dysfunction) and short-chain fatty acid oxidation (leading to ethylmalonic aciduria). Treatment with N-acetylcysteine and metronidazole can be helpful [30]. N-acetylcysteine is a precursor of glutathione, which can detoxify hydrogen sulphide, and metronidazole reduces the formation of hydrogen sulphide in the gut.

Palmoplantar keratoderma

Non-epidermolytic palmoplantar keratoderma has been reported in a number of families with the m.7445A>G mtDNA mutation [31]. All affected individuals have also had sensorineural hearing loss. There is diffuse or circumscribed epidermal thickening particularly over pressure points, such as the metatarsal heads, without intraepidermal blistering. Hyperkeratosis appears from mid-childhood onwards, the soles of the feet being affected earlier and more frequently than the palms. Skin biopsy shows orthokeratotic and parakeratotic hyperkeratosis with some acanthosis. Interestingly, the m.7445A>G mutation has been homoplasmic in all pedigrees but only 60% of individuals have had deafness and fewer than 40% have had keratoderma: other genetic or environmental factors must affect expression of the disorder. Palmoplantar keratoderma with deafness can also result from mutations in GJB2, which encodes a gap junction protein; these cases show autosomal dominant inheritance.

Other dermatological features

Several other dermatological abnormalities are associated with mitochondrial disorders but they are generally non-specific and overshaddowed by other symptoms. Hypertrichosis occurs in several disorders, particularly Leigh syndrome due to SURF1 mutations [32] but also in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome and infantile lactic acidosis due to SUCLG1 mutations. MELAS syndrome is one of the commoner mitochondrial disoders and is usually caused by a m.3243A>G mtDNA mutation. Erythema, ichthyosis, pruritus, reticular hyperpigmentation and poikiloderma have all been reported in patients with the m.3243A>G mutation [33] and in other mitochondrial disorders.

CONGENITAL DISORDERS OF GLYCOSYLATION

Congenital disorders of glycosylation (CDGs) are rare multisystem disorders, caused by defects in the glycosylation of proteins or lipids. Most are inherited as autosomal recessive traits. Much the commonest of these disorders is phosphomannomutase 2 deficiency (PMM2-CDG, i.e. the CDG involving the PMM2 gene), previously known as CDG type 1a. All PMM2-CDG patients have neurological involvement and many have dermatological features, such as peau d'orange, inverted nipples and fat pads [34]. Similar features occur in many other forms of CDGs.

Several other dermatological abnormalities can be found in CDGs. Ichthyosis occurs in SRD5A3-CDG, DOLK-CDG, PIGL-CDG, SRD5A3-CDG and COG5-CDG. Cutis laxa occurs in COG7-CDG, ATP6VOA2-CDG and MAN1B1-CDG. The progeroid variant of Ehlers–Danlos syndrome is caused by B4GALT7-CDG or B4GALT6-CDG. COG6-CDG is associated with hypohidrosis and EOGT-CDG is one of several causes for Adams–Oliver syndrome (aplasia cutis congenita of the scalp and terminal limb malformations). POFUT1-CDG is an autosomal dominant disorder that only affects the skin, causing hypopigmented macules and reticular hyperpigmentation. Finally, GALNT3-CDG is one of several causes for hyperphosphataemic familial tumoral calcinosis. These disorders are considered in reference [34].

Phosphomannomutase 2 deficiency

Incidence

The incidence of PMM2-CDG has been estimated at one in 40 000 in Sweden.

Pathophysiology

Most secreted and cell surface proteins are glycosylated. The oligosaccharides attached to proteins are high in mannose and PMM2 deficiency prevents their synthesis, leading to deficiency or dysfunction of numerous glycoproteins.

Genetics

PMM2-CDG is an autosomal recessive disorder caused by mutations in the PMM2 gene. Phosphomannomutase 2 catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is an essential substrate for synthesis of the carbohydrate moieties in glycoproteins. More than 90 PMM2 mutations have been identified, of which p.R141H is the commonest.

Clinical features

PMM2-CDG usually presents in the newborn period with hypotonia, internal strabismus and dysmorphic features [35]. Some patients have subcutaneous fat pads, usually located over the iliac crests in the superolateral portions of the buttocks, with lipodystrophy of the rest of the buttocks (Figure 81.8). They may also occur in the suprapubic area, lateral thighs or upper arms. The fat pads are most prominent in infancy and usually disappear later in childhood. The skin may have loose folds or feel thick and there may be peau d'orange; later, lipoatrophy can lead to streaks over the legs. The nipples are often inverted. Dysmorphic features may include large dysplastic ears and skeletal abnormalities, such as long fingers and toes.

Most patients have severe psychomotor retardation and are unable to walk. Feeding problems, poor growth, hepatomegaly and hypogonadism are also common. There is, however, a wide range of severity. Patients at the mild end of the spectrum have no dysmorphic or dermatological features and only mild learning difficulties.

Complications and prognosis

Complications may include stroke-like episodes, epilepsy, retinitis pigmentosa, severe infections, renal or hepatic impairment, cardiomyopathy and pericardial effusions. There is a high mortality (about 20%) in the first few years but subsequently the mortality is much lower and neurological regression is rare [35].

Investigations

Most CDGs, including PMM2-CDG, are initially diagnosed by transferrin isoelectric focusing. Serum transferrin is a glycoprotein and the attached oligosaccharides give it a negative charge; most disorders of glycosylation lead to abnormal patterns on transferrin isoelectric focusing. The next step is to measure PMM2 activity in leukocytes or fibroblasts.

Management

Unfortunately, there is no effective treatment for PMM2-CDG (or for most other CDGs).

DISORDERS OF AMINO ACID METABOLISM AND TRANSPORT

These are multisystem disorders in which problems result from the deficiency of an amino acid or from the toxic accumulation of an amino acid or a related chemical. Neurological problems are common and may be acute (encephalopathy or coma) or chronic (e.g. psychomotor retardation). The disorders are diagnosed by the analysis of amino acids (in plasma or urine) or organic acids (in urine). They are often treated with a special diet.

Amino acid disorders with dermatological features are summarized in Table 81.5 and some are considered in more detail below.

Table 81.5 Disorders of amino acid metabolism with dermatological features.

Disorder	Synonyms	Dermatological features	Other features
Phenylketonuria (PKU)	Phenylalanine hydroxylase deficiency	Hypopigmentation of skin and hair, eczema	Cognitive and behaviour problems, seizures
Tyrosinaemia type 2	Richner–Hanhart syndrome	Painful palmoplantar hyperkeratoses	Corneal ulcers, cognitive problems
Alkaptonuria		Pigmentation of pinna, sclera, skin and buccal mucosa	Arthritis
Prolidase deficiency		Ulcers, eczema, purpura, scarring, predisposition to SLE	Cognitive problems, facial dysmorphism, splenomegaly
Argininosuccinic aciduria	Argininosuccinate lyase deficiency	Trichorrhexis nodosa	Cognitive problems, hyperammonaemia
Hartnup disease		Photosensitive dermatitis	Cerebellar ataxia
Classical homocystinuria	Cystathionine β-synthase deficiency	Pale skin and hair, ulcers, livedo reticularis on legs	Cognitive problems, dislocated lenses, Marfanoid habitus, thromboembolism
Lysinuric protein intolerance		Predisposition to SLE	Poor weight gain and growth, osteopenia, hepatosplenomegaly, hyperammonaemia
Branched chain organic acidurias	Propionic, methylmalonic and isovaleric acidaemias	Desquamation, periorificial dermatitis, alopecia, psoriasiform lesions – may be due to excessive protein restriction	Acute encephalopathy and ketoacidosis, vomiting, cognitive problems

SLE, systemic lupus erythematosus.

Phenylketonuria

Introduction and general description

Phenylketonuria (PKU) is an inherited disorder affecting the degradation of phenylalanine and leading to high blood phenyl-alanine concentrations. Without treatment, it can cause severe neurodevelopmental problems.

Incidence

The incidence is about one in 12 000, although it varies from one country to another.

Pathophysiology

Genetics

In 99% of cases, PKU is due to defects of phenylalanine hydroxylase (PAH), the enzyme that catalyses the conversion of phenylalanine to tyrosine. The remaining patients have defects affecting the synthesis or recycling of tetrahydrobiopterin, the co-factor for PAH. All cases show autosomal recessive inheritance.

Clinical features

In most developed countries, PKU is detected by newborn screening and the classic clinical features are seldom seen. Without screening, patients present during infancy or early childhood, with psychomotor retardation and behaviour problems sometimes followed by seizures. Untreated patients have an increased incidence of eczema (20–40%) [36]. They also have reduced pigmentation of the hair, skin and iris [36]. Hair tends to be blonde in children who might otherwise have brown hair and it is brown in children expected to have black hair. White children often have blue irides. The altered pigmentation is caused by the impaired synthesis of melanin and improves with tyrosine supplements, indicating that it is at least partly due to tyrosine deficiency, although the high phenylalanine concentrations may also inhibit tyrosinase.

Investigations

Phenylketonuria is usually detected by newborn screening. Plasma amino acid analysis should be undertaken if the diagnosis is suspected in patients who have not had screening. If this suggests PKU, defects of tetrahydrobiopterin metabolism should be excluded and PAH mutation analysis may be undertaken.

Management

Phenylketonuria is treated by restriction of dietary phenylalanine. Most patients require a semi-synthetic diet, extremely low in natural protein, with a supplement containing all the amino acids except phenylalanine. Because phenylalanine is not synthesized in the body, this can bring the blood phenylalanine concentration down to levels that do not cause neurological damage. The diet also corrects the tyrosine deficiency, so treated patients have normal pigmentation.

The damage caused by high phenylalanine levels diminishes with age and, for this reason, the target phenylalanine concentrations are less strict in older children and adults. Indeed, many adults revert to a normal diet without major problems, though there is a risk of nutritional deficiencies. Strict dietary treatment is essential during pregnancy to avoid adverse effects on the fetus. Adults who stop dietary treatment may have a slightly increased risk of eczema [37] but low tyrosine concentrations and hypopigmentation are not seen.

Pharmacological doses of tetrahydrobiopterin can lower blood phenylalanine concentrations in some patients with PAH deficiency [38]. These patients generally have relatively mild PKU with some residual enzyme activity. Most of them continue to require some dietary phenylalanine restriction in addition to treatment with tetrahydrobiopterin.

Different treatment is required for defects of tetrahydrobiopterin synthesis or recycling. Patients need neurotransmitter precursors and, for most of the defects, tetrahydrobiopterin is used rather than a special diet.

Tyrosinaemia type 2

Introduction and general description

Tyrosinaemia type 2 is caused by deficiency of tyrosine aminotransferase, which catalyses the first step in tyrosine degradation. The eye, skin and brain can be affected but a number of patients are probably asymptomatic. Corneal ulcers occur in approximately 75% of patients presenting clinically, painful palmoplantar hyperkeratoses occur in 80% and learning difficulties in 60%. Manifestations may vary within a single pedigree.

Incidence

Tyrosinaemia type 2 is very rare but more than 50 cases have been reported, many of Italian ancestry.

Pathophysiology

The ophthalmological problems are thought to result from tyrosine crystals precipitating in corneal epithelial cells, disrupting lysosomes and leading to inflammation [39]. In contrast, skin biopsies show no tyrosine crystals and minimal inflammation. There is hyperkeratosis, acanthosis and parakeratosis with homogeneous refractile eosinophilic inclusions in the stratum corneum and upper Malpighian layer. Electron microscopy shows keratinocytes with increased tonofibrils and microtubules [39].

Genetics

This autosomal recessive disorder is caused by mutations in the TAT gene.

Clinical features

Patients usually present with photophobia and eye pain, often in the first year, although adult onset has been reported. The eye is red with lacrimation and slit lamp examination shows dendritic corneal erosions that resemble herpetic ulcers. Without treatment, corneal scarring may lead to permanent visual loss and glaucoma.

Typically, skin problems appear after the first year [40]. Painful hyperkeratotic plaques appear on the palms and soles, including the digits. They are usually found at pressure points, such as the fingertips. The lesions may start as blisters and may ulcerate (Figure 81.9). There may be hyperhidrosis of the palms and soles and leukokeratosis of the tongue.

Learning difficulties are thought to occur in about 50% of patients but the severity varies. Some patients have severe cognitive impairment and difficult aggressive behaviour. Others have mild neurological problems, such as poor fine coordination.

Differential diagnosis

Tyrosinaemia type 3 is due to the deficiency of 4-hydroxyphenylpyruvate dioxygenase. Tyrosine concentrations tend to be lower than in tyrosinaemia type 2, although there is considerable overlap. Some patients have mental retardation but no skin or eye problems occur.

Tyrosinaemia type 1 is caused by fumarylacetoacetase deficiency and leads to severe liver disease and renal tubular dysfunction. Tyrosine concentrations are moderately elevated and, though they rise further on treatment with nitisinone, there have been no reports of skin lesions like those of tyrosinaemia type 2

Investigations

Amino acid analysis shows marked increased plasma tyrosine concentrations, often above 1200 μmol/L, although they may be as low as 400 μmol/L on a normal diet. The diagnosis is now usually confirmed by mutation analysis.

Management

The treatment of tyrosinaemia type 2 is dietary. In some patients, a low protein diet leads to acceptable tyrosine concentrations; others need a more severe protein restriction and an amino acid supplement free of tyrosine and phenylalanine. The eye and skin problems resolve if the plasma tyrosine concentrations are kept below 800 μmol/L, but the neurological problems may deteriorate and most centres have target levels below 500 μmol/L.

Alkaptonuria

Introduction and general description

Alkaptonuria is a very rare inherited disorder caused by homogentisate dioxygenase deficiency. The main problems are backache and arthritis starting in adulthood.

Incidence

Alkaptonuria is very rare (1 : 250 000 to 1 : 1 000 000).

Pathophysiology

Homogentisate dioxygenase catalyses the third step in tyrosine degradation. Its deficiency leads to the accumulation of homogentisic acid and its oxidized derivative, benzoquinone acetic acid. This can be polymerized to form a dark pigment, which is deposited in connective tissue. The cause of arthritis is uncertain but the pigment may act as a chemical irritant.

Genetics

This is an autosomal recessive disorder caused by mutations in the HGD gene.

Clinical features

Most patients present with low back pain between 25 and 40 years of age [41]. This progresses to kyphosis and, often, ankylosis. Other patients present with arthritis in the hip or knee. Many patients require a joint replacement and some become bedridden. Older patients often develop calcification of the aortic or mitral valves or coronary arteries.

Children are asymptomatic but their urine darkens after a few hours, particularly if it is alkalinized. Cloth nappies may, therefore, turn black when washed, as may contaminated clothes and sheets. Ochronosis (melanin-like black pigmentation) may be seen from the age of 30 years onwards. The cartilage of the ears develops grey or blue-black discoloration and feels thick and inflexible [41]. Cerumen may be brown or black. Brown or grey deposits also appear in the sclera, typically mid-way between the medial canthus and the cornea [41]. Pigment may also be seen in the buccal mucosa and the nails are sometimes brown. There may be dusky discoloration of the skin, especially over the cheeks, forehead, axillae and genital region.

Investigations

The diagnosis is established by urine organic acid analysis, which reveals homogentisic acid.

Management

As yet, no treatment has been shown to prevent the long-term complications of alkaptonuria. Nitisinone inhibits the first step in tyrosine breakdown and, even at low doses, it reduced plasma and urine homogentisic acid by 95%. Unfortunately, a 3-year controlled trial in adults showed no difference in the progression of joint disease, possibly because the arthropathy was already too advanced before treatment [42].

Prolidase deficiency

Introduction and general description

Prolidase deficiency is caused by an inability to break down imidodipeptides and is characterized primarily by skin lesions, especially ulcers. No specific treatment is known to help.

Incidence

It is very rare: about 80 patients have been reported.

Pathophysiology

Prolidase is needed to degrade dipeptides with an N-terminal proline or hydroxyproline. It is uncertain how the accumulation of imidodipeptides causes the clinical problems.

Genetics

This is an autosomal recessive disorder due to mutations in the PEPD gene.

Clinical features

Patients have presented at any time from birth up to 22 years of age and it is possible that some may remain asymptomatic throughout life. Recurrent ulcers are the commonest problem, mostly on the lower legs (Figure 81.10) [43]. The skin is fragile and the ulcers sometimes follow an injury. The ulcers are resistant to treatment and may be complicated by secondary infection. Other skin problems include dermatitis (with crusting), fine scarring, telangiectasia, purpura or bruising (Figure 81.11). There may be lymphoedema or a doughy consistency to the skin. Many patients have psychomotor retardation and some have a characteristic facial appearance, with hypertelorism and a shallow nasal bridge [44]. There may be recurrent infections or chronic lung disease resembling cystic fibrosis. Other features include splenomegaly, anaemia, thrombocytopenia or hypergammaglobulinaemia; there is an increased risk of systemic lupus erythematosus [44, 45].

Investigations

Plasma or urine amino acid analysis shows various imidodipeptides. The diagnosis is now confirmed by mutation analysis.

Management

No specific treatment is known to help, although there have been anecdotal reports of success with various agents, including ointments containing glycine and proline or systemic ascorbic acid or manganese (the co-factor of prolidase). Skin grafts have been unsuccessful. Infections should be treated aggressively.

Argininosuccinic aciduria

Introduction and general description

Argininosuccinic aciduria (ASA) is a rare urea cycle disorder. It may present acutely, with hyperammonaemia, or chronically, with learning difficulties and trichorrhexis nodosa (Figure 81.12).

Incidence

Its incidence is approximately one in 70 000.

Pathophysiology

Episodes of encephalopathy in ASA are primarily caused by hyperammonaemia. It has been suggested that the trichorrhexis nodosa may be due to chronic arginine deficiency. This seems unlikely as arginine deficiency occurs in most urea cycle disorders but abnormal hair is only found in ASA. Argininosuccinate lyase stabilizes nitric oxide synthase and some of the long-term complications may be due to nitric oxide deficiency [46].

Genetics

This is an autosomal recessive disorder caused by mutations in the ASL gene.

Clinical features

Many patients present with vomiting, confusion or coma due to acute hyperammonaemia. This often occurs 12–72 h after birth, although it can happen at any age.

Patients with residual enzyme activity often present at a few years of age, with learning difficulties and thinning of the hair, which is dry and brittle. Examination with a microscope reveals nodular swellings on the hair shafts and frayed cortical fibres, consistent with trichorrhexis nodosa [47].

Prognosis

Even with treatment, most patients have learning difficulties and those with severe defects develop neurological problems, epilepsy and chronic liver disease.

Investigations

Argininosuccinic acid is best detected by urine amino acid analysis, although it is also present in plasma.

Management

Treatment involves dietary protein restriction and drugs (sodium benzoate and/or sodium phenylbutyrate). l-arginine is also given to correct the deficiency of this amino acid and to facilitate the excretion of ammonia (incorporated into argininosuccinic acid). These measures prevent hyperammonaemia and lead to resolution of the trichorrhexis nodosa.

Hartnup disease

Introduction and general description

Hartnup disease is caused by the deficiency of a neutral amino acid transporter in the epithelial cells of the renal tubule and intestine. It presents in childhood with a pellagra-like rash and neurological problems but many patients remain asymptomatic.

Incidence

The incidence on newborn screening has ranged from 1 : 14 000 to 1 : 45 000 but the number of patients presenting clinically is much lower.

Pathophysiology

Nicotinamide is essential for many reactions (see Chapter 63) and can be formed from dietary niacin or from tryptophan. In patients with Hartnup disease, impaired intestinal absorption of tryptophan (a neutral amino acid) leads to a reduced synthesis of nicotinamide. The absence of symptoms in some patients may reflect their dietary niacin intake or the absorption of tryptophan in oligopeptides [48].

Genetics

This is an autosomal recessive disorder caused by mutations in the SLC6A19 gene.

Clinical features

Patients usually present with a rash between 3 and 9 years of age. Well-demarcated, dry, scaly patches occur on sun-exposed skin, such as the face, backs of the hands and exposed parts of the arms. Exposure to sunlight causes erythema, sometimes with blistering, and may be followed by desquamation and depigmentation [49]. Cerebellar ataxia is the commonest neurological problem and starts after the rash. There may also be nystagmus, tremor, weakness or psychiatric symptoms.

Prognosis

Symptoms tend to improve with age, even without treatment.

Investigations

There are increased neutral amino acids in the urine with low or low–normal concentrations in the plasma.

Management

The rash and neurological problems generally resolve with oral nicotinamide (50–300 mg/day). A high protein diet is also recommended.

DISORDERS OF CHOLESTEROL SYNTHESIS

There are a number of inborn errors affecting cholesterol synthesis. Two of these cause dermatological problems that include ichthyosis and they are discussed in other chapters. These disorders are sterol Δ⁸-Δ⁷ isomerase deficiency (X-linked dominant chondrodysplasia punctata or Conradi–Hünermann syndrome) (see Chapter 65) and 3β-hydroxysteroid C-4 dehydrogenase deficiency (CHILD syndrome) (see Chapter 65).

Smith-Lemli-Opitz syndrome

This is an autosomal recessive disorder resulting from 7-dehydrocholesterol reductase deficiency. It is much the commonest disorder of cholesterol synthesis, with an incidence of between 1 : 15 000 and 1 : 60 000 in white people. There is a wide range of severity: most patients have facial dysmorphism, 2/3 syndactyly of the toes, undescended testes, failure to thrive, microcephaly, mental retardation and autism. The main dermatological problem is photosensitivity, which may be severe [50]. Other features may include hypopigmented hair, hyperhidrosis of the palms, eczema, cutis marmorata and acrocyanosis [51]. The diagnosis is made by demonstrating elevated plasma 7-dehydrocholesterol levels. Treatment with cholesterol does not alter the cognitive outcome but it is said to improve the photosensitivity [52].

Mevalonate kinase deficiency

Mevalonate kinase deficiency is a much rarer autosomal recessive disorder with a wide range of severity. In mildly affected patients, the only problems are episodes of fever and inflammation, which may happen every 4–6 weeks, with high levels of IgD [53]. Erythematous maculopapular rashes occur during these episodes, along with lymphadenopathy, arthralgia and abdominal pain [54]. Severely affected patients have dysmorphism, failure to thrive and mental retardation, in addition to the episodes of inflammation [55]. The diagnosis is made by demonstrating mevalonic acid on urine organic acid analysis; this may only be present during crises in mildly affected patients. There is no specific treatment.

OTHER METABOLIC DISORDERS

Lesch–Nyhan syndrome

Introduction and general description

Lesch–Nyhan syndrome is an X-linked disorder caused by hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. It is characterized by neurological and psychological problems, with compulsive self-mutilation, and complications of hyperuricaemia.

Incidence

Lesch–Nyhan syndrome is very rare (approximately 1 : 400 000).

Pathophysiology

A central role is played by HPRT in the generation of purine nucleotides through the purine salvage pathway. The neurological symptoms are associated with the impaired development of dopaminergic neurons, but how the biochemical defect causes this remains unknown [56].

Genetics

This is an X-linked recessive disorder due to mutations in HPRT1. A few affected females have been reported due to skewed pattern of inactivation of the X chromosome.

Clinical features

Patients present after 4 months of age with delayed motor milestones, followed by chorea, spasticity and dysarthria [57]. Subsequently, they develop a compulsion to injure themselves, although they have normal pain sensation. Biting can lead to self-amputation of fingers or parts of the lips. They may also be aggressive to other people, both physically and verbally. The IQ is usually around 60–70 and many patients have seizures. Without treatment, patients develop renal uric acid stones but gouty arthritis and tophi are rarer.

Clinical variants

Lesch–Nyhan syndrome is only seen with complete (or near complete) HPRT deficiency. Partial deficiency causes gout but seldom any neurological problems.

Investigations

Uric acid excretion is increased, as is the plasma urate concentration in most patients, although the latter is occasionally normal before puberty. The diagnosis can be confirmed by measuring HPRT activity in erythrocytes.

Management

Allopurinol is given to prevent urate nephropathy but it does not affect the neurological problems, for which there is only symptomatic treatment. Self-mutilation can be reduced by restraints (such as elbow splints and lip guards) or extraction of the teeth.

Disorders of biotin metabolism

Introduction and general description

Biotin, a water-soluble vitamin, is the co-factor for four carboxylase reactions involved in amino acid degradation, gluconeogenesis and fatty acid synthesis. Holocarboxylase synthetase is needed to bind biotin to the apoenzymes. Biotinidase is needed for the recycling of biotin and the use of dietary protein-bound biotin. Deficiency of either biotinidase or holocarboxylase synthetase leads to multiple carboxylase deficiency. The clinical features vary but may include episodes of acidosis, seizures, rashes and alopecia.

Incidence

The incidence of severe biotinidase deficiency is about 1 : 100 000. Partial deficiency has approximately the same frequency but its clinical significance is debatable.

Pathophysiology

Genetics

Biotinidase and holocarboxylase synthetase deficiencies are both autosomal recessive disorders.

Clinical features

Holocarboxylase synthetase deficiency usually presents in the first days of life with vomiting, lethargy, lactic acidosis and ketoacidosis and hyperammonaemia; without treatment, this leads to coma and death. Patients with some residual enzyme activity may present later in childhood with similar symptoms or with developmental impairment, hair loss or rashes. The rash is usually widespread, erythematous and scaly, particularly affecting the napkin area. It may resemble ichthyosis or seborrhoeic dermatitis [58].

Biotinidase deficiency usually presents between 2 and 6 months of age, although symptoms may occur earlier and a few patients present later in childhood [59, 60]. The initial features are usually hypotonia and seizures (generalized tonic clonic or myoclonic). Patients also have psychomotor retardation, hearing loss and visual impairment due to optic atrophy. Dermatological problems are common but may be delayed [60]. Most patients develop a patchy erythematous or exudative rash, particularly around the mouth. The rash may be widespread and there may be skin infections, conjunctivitis, blepharitis or onychoschizia. Hair is sparse and some patients have complete alopecia, including loss of eyelashes and eyebrows.

Biotinidase deficiency is diagnosed by newborn screening in some countries.

Investigations

Patients with holocarboxylase synthetase deficiency generally excrete characteristic organic acids, including lactate, 3-hydroxyisovalerate, 3-hydroxypropionate, methylcitrate and 3-methylcrotonylglycine.The diagnosis is confirmed by mutation analysis or by measuring carboxylase activities in fibroblasts at low or high biotin concentrations.

In biotinidase deficiency, the organic acids may be normal or only show increased 3-hydroxyisovalerate. The disorder is easily diagnosed, however, by measuring biotinidase activity in plasma.

Management

In patients with biotinidase deficiency, the seizures and dermatological problems respond promptly to treatment with biotin (5–10 mg/day). Unfortunately, unless treatment is started early, cognitive, hearing and visual problems are likely to persist.

Most patients with holocarboxylase synthetase deficiency respond to biotin at 10–20 mg/day but some require higher doses. A few patients only show a partial response and they may have learning difficulties despite early treatment.

Acrodermatitis enteropathica

Introduction and general description

This is an inherited disorder affecting the intestinal absorption of zinc. The resulting zinc deficiency leads to dermatitis, alopecia and diarrhoea.

Incidence

Acrodermatitis enteropathica is very rare (approximately 1 : 500 000).

Pathophysiology

Acrodermatitis enteropathica is caused by defects in ZIP4, the main intestinal zinc transporter. Zinc is a co-factor for many enzymes. The skin, intestine and immune system are most severely affected because of their rapid cell turnover.

Pathophysiology

Genetics

This is an autosomal recessive disorder caused by mutations in SLC39A4, a gene that encodes ZIP4.

Clinical features

Patients present with apathy or irritability and a rash around the mouth and anus and on the hands and feet [61]. Symptoms start after weaning in breastfed babies and at 4–10 weeks of age if they are formula-fed. Erythema progresses to vesicles, bullae, pustules, desquamation and crusting (Figure 81.13). There is alopecia and frequently blepharitis, conjunctivitis and photophobia. Infections are common, including secondary infections of the skin, for example with Candida albicans. Wound healing is poor and many patients have diarrhoea and growth faltering. Without treatment, the condition can be fatal but some patients survive into adulthood.

Differential diagnosis

Similar problems occur in zinc deficiency due to other causes, such as gastrointestinal disorders. Biotinidase deficiency and protein malnutrition lead to a similar rash.

Investigations

The serum zinc concentration is usually low but can be normal [61]. Decreased zinc absorption can be demonstrated using radioisotopes but it is easier to undertake a trial of zinc therapy: patients respond within a week. Acquired zinc deficiency can be excluded by observing a relapse after stopping treatment. SLC39A4 mutation analysis is becoming more widely available.

Management

Patients respond to oral zinc sulphate within a few days [62]. The normal dose is 150–400 mg/day in childhood; a lower dose may suffice after puberty but 400–500 mg/day is needed during pregnancy. If zinc sulphate causes gastric problems, other zinc salts or encapsulated preparations have been recommended but they are not widely available. Monitoring for copper deficiency should be undertaken.

Menkes disease and occipital horn syndrome

Introduction and general description

Menkes disease is an X-linked disorder in which copper deficiency leads to neurodegeneration, ‘kinky hair’ and connective tissue abnormalities. Occipital horn syndrome is an allelic variant with connective tissue abnormalities but no neurodegeneration.

Incidence

Both these diseases are very rare (approximately 1 : 250 000).

Pathophysiology

Menkes disease is caused by mutations in ATP7A, encoding a transporter for copper. This defect prevents the transport of copper from the intestinal mucosa into the portal circulation and leads to copper deficiency. Copper is needed for many enzymes, including lysyloxidase (which is involved in collagen cross-linking) and tyrosinase (which is necessary for melanin synthesis). The neurological problems can be explained by the role of copper in mitochondrial function and neurotransmitter synthesis.

Genetics

These X-linked recessive disorders are caused by ATP7A mutations.

Clinical features

Boys with Menkes disease typically present at 2–3 months with hypotonia and seizures. Developmental regression and spasticity appear later in the first year. The hair is usually normal for the first few weeks but soon becomes sparse and brittle. In typical cases, there is scanty colourless or blond hair over the vertex with stubble elsewhere (Figure 81.14); in milder cases, the hair may be pigmented with occipital baldness due to trauma. Microscopic examination reveals pili torti and occasionally trichorrhexis nodosa [63]. Patients acquire a characteristic facial appearance with sagging cheeks and frontal bossing. The skin is loose, especially on the back of the neck. Diarrhoea, osteoporosis and subdural haemorrhages are common. Untreated patients generally die by 3 years of age.

Clinical variants

Occipital horn syndrome is a mild variant with demineralization and exostoses, especially over the occiput, hence the name of the syndrome [64]. The skin and joints are lax and the disorder was previously called X-linked cutis laxa. Patients often have diarrhoea or urine infections due to bladder diverticulae. There may be mild learning difficulties but other neurological problems and pili torti are rare.

Investigations

Low serum copper and caeruloplasmin concentrations are only diagnostic after 3 months of age; low levels can be found in normal babies below this age. The diagnosis is now confirmed by mutation analysis.

Management

Daily subcutaneous injections of copper histidine can improve the outcome, but only if started within a month of birth [65]. Even with early treatment, patients with severe mutations have psychomotor retardation. Copper histidine injections do not correct the connective tissue abnormalities.

Wilson disease

Introduction and general description

In Wilson disease, copper accumulation leads to hepatic or neuropsychological problems; the dermatological features are mild. Patients usually present as children or young adults. Though there is treatment, neurological problems often persist.

Incidence

The incidence of Wilson disease is 1 : 30 000 to 1 : 100 000.

Pathophysiology

In Wilson disease, deficiency of a copper-transporting ATPase reduces the excretion of copper in bile and its incorporation into caeruloplasmin. Copper accumulates in the liver and, subsequently, in the brain, kidney and other tissues.

Genetics

Wilson disease is an autosomal recessive disorder caused by ATP7B mutations.

Clinical features

Hepatic presentations usually occur between 8 and 20 years of age. They may be acute, with hepatitis and liver failure, or insidious with cirrhosis. Neurological manifestations usually occur between 12 and 30 years of age; dysarthria and deteriorating handwriting are early symptoms, followed by tremor, dystonia and drooling. Some patients present with behavioural changes or psychosis. Other problems may include renal tubulopathy or haemolytic anaemia. A brown Kayser–Fleischer ring may be seen at the limbus of the cornea, particularly in patients with neurological symptoms.

Dermatological features are common but not troublesome. Blue lunulae of the nails are the most specific finding and are said to be present in 10% of adult patients at diagnosis. Commoner findings include xeroderma and grey-brown hyperpigmentation, especially on the extensor surfaces of the legs, and cheilitis [66]. There may also be pruritus or spider naevi due to the liver disease or rashes due to drug treatment.

Investigations

Serum copper and caeruloplasmin concentrations are generally low, with raised 24 h urine copper excretion (particularly after a dose of penicillamine) and raised liver copper. None of these tests, however, have 100% sensitivity or specificity and ATP7B sequencing is undertaken increasingly often [67].

Management

Treatment promotes copper excretion using chelators (penicillamine, trientine or tetrathiomolybdate) or zinc, which increases the faecal excretion of copper bound to metallothionein [68]. Penicillamine is recommended in patients with liver disease: most recover but a few require liver transplantation. For patients who are pre-symptomatic or have neurological symptoms, zinc is often used as it has fewer side effects. Unfortunately, the neurological problems seldom resolve completely and, indeed, there is often an initial deterioration on treatment.

Familial tumoral calcinosis

Introduction and general description

Ectopic calcification in the skin is termed cutaneous calcinosis. Acquired ectopic calcification in the skin is traditionally classified into metastatic and dystrophic cutaneous calcinosis [69, 70]. In metastatic calcinosis, as seen in chronic renal failure, calcium deposits result from elevated blood levels of calcium and/or phosphate. In dystrophic calcinosis, typically associated with autoimmune diseases, atherosclerosis and cancer [71, 72], the calcified material accumulates following some form of primary tissue damage (see Chapter 61).

Clinical features

The hereditary counterpart of acquired metastatic calcification is termed hyperphosphataemic familial tumoral calcinosis (HFTC). The disease manifests with the formation of often large, calcified masses located mainly over the large joints [73]. These masses are located deep into the dermis and subcutaneous tissues and can affect joint mobility. They cause pain and can become secondarily infected. Calcifications can also involve visceral organs and teeth [73]. HFTC results from loss-of-function mutations in one of three genes: FGF23, encoding a potent phosphaturic protein, KL, encoding Klotho, a co-receptor for FGF23, and GALNT3, encoding a glycosyltransferase responsible for mediating a physiologically critical post-translational modification of FGF23 [73–76].

The inherited equivalent of dystrophic calcification is termed normophosphataemic familial tumoral calcinosis (NFTC). Patients affected with this disease present with a vasculitis-like rash at a young age, followed years later by the appearance of calcified masses in the cutaneous and subcutaneous tissues (Figure 81.15) [73, 77]. The calcified lesions are smaller and more superficially located in NFTC than in HFTC, and therefore tend to perforate the skin, leading to painful ulcers and secondary infections. Additionally, patients display severe inflammatory manifestations in mucosal tissues. NFTC is caused by mutations in the sterile alpha motif domain 9 (SAMD9) gene [77, 78]. SAMD9 may function physiologically as a tumour suppressor gene [79] as overexpression of SAMD9 causes apoptosis and reduced proliferation of malignant cells, while down-regulation of SAMD9 is associated with increased cellular proliferation and tumour growth [79], and haematological cancers are associated with SAMD9 deletion [80]. Tumour necrosis factor-α and interferon-γ induce SAMD9 expression which regulates EGR-1 [81, 82], a transcription factor with a known role in the regulation of tissue calcification, inflammation and cell migration [78, 83, 84].

Calcinosis cutis can occur in other genodermatoses including Albright hereditary osteodystrophy, Rothmund–Thomson syndrome, hereditary sclerosing poikiloderma, pseudoxanthoma elasticum and acquired diseases (see Chapter 61).

Management

The surgical removal of calcified masses is required in the presence of significant functional impairment or unacceptable cosmetic appearance. Treatment with phosphate binders has been mostly disappointing in patients with HFTC but acetazolamide may be of benefit [85].

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