Dermatologic Manifestations of Homocystinuria Clinical Presentation

Updated: May 17, 2022
  • Author: Janette Baloghova, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Neurologic features

An infant with homocystinuria is usually healthy, although thromboembolic complications of the CNS and psychomotor delay may occur during the first year of life.

Alehan et al reports a case of a previously healthy girl, age 3 years 9 months, who presented with right-sided hemiparesis and seizures. Ischemic infarction was confirmed through MRI and magnetic resonance angiography. Based on the clinical and laboratory results, a diagnosis of homocystinuria was made. Homocystinuria is an inherited disorder that affects the metabolism of the amino acid methionine. Although homocystinuria is usually associated with ischemic strokes, the sudden onset of stroke as the initial clinical presentation of homocystinuria is very rare in early childhood. Based on this case, however, metabolic screening for hyperhomocystinemia is recommended in any child presenting with a stroke. [25]

A developmental delay is noted when patients are aged 2-3 years.

Pyramidal symptoms, including muscle weakness due to an insult to the innervation of the pyramidal motor tract neurons, are occasionally observed in areas such as the leg.

Homocystinuria should be included in the differential diagnosis of children with acute/subacute neurological changes, particularly in the context of developmental delay.

Skeletal and muscular features

The characteristic long thin extremities and arachnodactyly may not appear until late in childhood or during adolescence. In contrast, osteoporosis, especially that of the spine, may have already been present for some time.

Ophthalmologic features

Severe myopia is the first sign of ectopia lentis and may precede lens dislocation by several months to a year or even longer. Once established, ectopia lentis progresses, even when good biochemical control is maintained.

Vascular features

Thromboembolic events, such as cerebrovascular occlusions or pulmonary emboli, usually do not occur until adulthood but are reported in childhood and infancy.

Homocystinuria can be a cause of cerebral sinovenous thrombosis in early childhood or it can be recognized later in adolescence as a cause of cerebral venous thrombosis. [26, 27]

Vascular occlusive disease is an important and serious feature.

Other features

Psychiatric symptoms are also described in approximately half the patients with homocystinuria. The most common are psychiatric disturbances such as depression, behavioral disorders, personality disorders, obsessive-compulsive disorder, and, less commonly, bipolar disorder and psychosis. [28]

Capgras syndrome (delusional misidentification syndrome [DMS]) was reported in a 42 year-old woman with homocystinuria. It is assumed that neuronal dysfunction mediated by the N-methyl-D-aspartate (NMDA) receptor may be involved in DMS. [29]

Acute psychosis was described in a 17-year-old girl affected by cystathionine beta-synthase (CBS) deficiency presenting as an acute onset of visual hallucinations, behavioral perseverance, psychomotor hyperactivity, and affective inappropriateness. Ectopia lentis, diagnosed several years before, was  not considered as possible sign of a metabolic disorder. Psychotic symptoms were unresponsive to the conventional antipsychotic drugs and were only relieved after pyridoxine and folic acid treatment. [30]


Physical Examination

Marfan syndrome is the primary differential diagnosis. Clinical features of homocystinuria, such as ectopia lentis, dolichocephalia, and chest and spinal deformities, are similar to the features found in patients with Marfan syndrome, although the cerebral symptoms, the changes in the hair, and the disorders of mental development are absent in patients with Marfan syndrome. Generalized osteoporosis, arterial and venous thrombosis, and mental retardation, which are features of homocystinuria, do not occur in patients with Marfan syndrome. In addition, homocysteine is not detectable in the urine of patients with Marfan syndrome.

Skin findings

Buccal skin shows red macules in children, adolescents, and adults, especially those living in warm environments.

Large pores are evident on the facial skin.

A livedolike pattern of blood vessels and atrophic, small, cigarette paper–like scars may be observed on the arms and hands.

Angiomata may develop in some patients.

DL-homocysteine inhibits tyrosinase, the major pigment enzyme. Hypopigmentation may be reversible in patients with pyridoxine-responsive homocystinuria.

Pigmentary dilution is observed in patients with homocystinuria. Therefore, an increase of local homocysteine may interfere with normal melanogenesis and may play a role in the pathogenesis of vitiligo. Vitamin B-12 and folic acid, levels of which are decreased in persons with vitiligo, are important cofactors in the metabolism of homocysteine. Shaker and El-Tahlawi found out that an elevated homocysteine level was higher in male patients than in female patients and higher in patients with progressive disease. [31] No significant difference in homocysteine levels was found between either untreated vitiligo patients or patients receiving UV therapy. An elevated homocysteine level may be a precipitating factor for vitiligo in predisposed individuals.

Goswami et al describe a case report of a 6-year-old boy with homocystinuria and cerebral sinovenous thrombosis (CSVT) who had hyperpigmentation over the dorsa of the fingers, axilla, and groin. [27]

Thin, dry, fine, light hair is characteristic. Hair stained with acridine orange produces orange-red fluorescence, whereas healthy hair produces green fluorescence.

Other cutaneous findings include livedo reticularis, hyperhidrosis, or dry pale skin, as well as possible acrocyanosis. Skin can be translucent with a tendency to develop eczema.

Neurologic findings

Patients may behave aggressively.

Intelligence is slightly diminished, but in approximately one third of patients, intelligence is in the normal range.

Patients' mental capabilities have been reported to be higher in conditions that respond to pyridoxine supplementation than others.

Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency may manifest with variable neurologic manifestations. Radiologic features include white matter changes (leukoencephalopathy). [32]

Muscular hypotonia is characteristic.

Increased homocysteine levels have been detected in persons with neurological disorders such as Alzheimer disease, idiopathic Parkinson disease, Huntington disease, primary dystonia, and neural tube defects.

Skeletal and muscular findings

Signs of Marfan syndrome, such as thin and long extremities, arachnodactylia, kyphoscoliosis, and deformations of the thorax, may be present.

Homocystinuria is associated with low bone mineral density, which can lead to osteoporosis. [33]

Genua valga, pectus carinatum (excavatum), and deformed teeth can be present.

The homocysteine concentration is an important risk factor for hip fractures in Parkinson disease patients receiving levodopa. [34]

Inguinal and umbilical hernias are observed.

Muscular hypotonia is characteristic.

Spasms may occur.

Ophthalmologic findings

Ophthalmologic findings are similar to those in patients with Marfan syndrome.

Ectopia lentis is an almost universal feature in patients older than 10 years, and it can even be present in newborns.

Other findings include myopia, iridopathy, cataracts, secondary glaucoma, and degeneratio (amotio) retinae.

Atrophy of the optic nerve, strabismus, nystagmus, or diminished convergence can occur in some patients.

Dislocation of the ocular lenses usually occurs in patients aged 4-10 years.

The lens is usually displaced either inferiorly or inferonasally. Superonasal displacement is rare. Comparing other inheritable disorders that can be associated with ectopia lentis (Marfan syndrome, Ehlers-Danlos syndrome, Weil-Marchesani syndrome, Treacher Collins syndrome) in homocystinuria, the lenses are significantly more mobile and tend to dislocate frequently. [35]

Ocular phenotype in patients with cblC is variable. [36] Ocular involvement seems to be correlated with age at onset. Patients with early-onset cblC developed generally progressive retinal disease ranging from subtle retinal nerve fiber layer loss to advanced macular and optic atrophy with bone-spicule pigmentation. Patients with late-onset disease showed no definite evidence of retinal degeneration.

Retinal dysfunction in cblC disease may be more common than previously thought and can involve cones only or both rods and cones. Gaillard et al recommend a formal ocular examination with full-field electroretinography in patients with Cblc disease. [37]

Montalvo et al report a case of a male infant affected by a familial exudative vitreoretinopathy (FEVR)‒like presentation of homocystinuria that resolved with treatment of the homocystinuria. A complete ocular examination on patients with homocystinuria should be performed to rule out or diagnose retinal abnormalities. Angiography, including wide-field angiography, can be considered to evaluate retinal abnormalities with a vascular component. [38]

Vascular findings

Vascular changes mainly affect the lower extremities. Fatal arterial and venous thromboses may occur.

Hyperhomocysteinemia is an independent risk factor for atherosclerotic heart disease and pulmonary embolism. One third of patients have a thrombotic event, typically before age 30 years. [39]

Patients with homocystinuria resulting from a deficiency of cystathionine beta-synthase have an increased risk of thrombosis when they also have the Leiden mutation for factor V.

Homocysteine induces tissue factor procoagulant activity in cultured human endothelial cells.

Reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen have been noted in patients with homocystinuria.

Goswami et al present a case report of a 6-year-old boy with homocystinuria and CSVT. The most common sites of CSVT are the transverse, superior sagittal, sigmoid, and straight sinuses. This child had involvement of the right transverse and superior sagittal sinuses. [40]

Oral and craniofacial findings

D’Alessandro et al reports a case of an 11-year-old patient with methylmalonic aciduria and homocystinuria, which developed during the neonatal period. [41]

The patient showed some facial features previously reported in the literature (high forehead, large floppy, low-set ears, flat philtrum, hypotonia of perioral and masticatory muscles), but no dolichocephalic skull nor long face.

The patient also showed signs that had not been previously described: epicanthal folds, broad nasal bridge, long and flat philtrum, amimic expression and, particularly, a postural alteration (the head is rotated and bent towards the left shoulder, which is lower than the right one).

Such alteration can be attributed to visual impairment and is responsible for breaking muscular and skeletal balance in the frontal plane, thus causing the horizontal planes of both maxillary bones to converge towards the right.

Other findings

A slightly foul odor of the urine is typical.

Spontaneous pneumothorax is reported in some adolescents with homocystinuria.

Pancreatitis is described as a complication of homocystinuria.

Increased homocysteine levels are implicated in a variety of other clinical conditions, including neural tube defects, spontaneous abortion, placental abruption, renal failure, diabetic microangiopathy, and premenstrual syndrome.

Children with autism might have lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of S-adenosylhomocysteine (SAH), adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism. [42]

Cystathionine beta-synthase is encoded on chromosome 21, and deficiency in its activity causes homocystinuria. The most common genetic cause of mental retardation is trisomy 21 or Down syndrome. The levels of cystathionine beta-synthase in the brains of persons with Down syndrome are approximately three times greater than those in healthy individuals. [43] The over-expression of cystathionine beta-synthase may cause the developmental abnormality in cognition in Down syndrome children and that may lead to Alzheimer-type disease in Down syndrome adults.

Vascular disease is associated with increased plasma asymmetric dimethylarginine and homocysteine, and levels of both are increased in persons with renal failure. The relationship between hyperhomocysteinemia and increased plasma asymmetric dimethylarginine may not be direct, but could be secondary do reduced renal function. [44]

Snyderman reports a case of a homocystinuric patient with development of paraparesis and increasing liver failure. [45] A liver transplantation was successful in achieving metabolic control without the need for any dietary restrictions.

Muacevic-Katanec et al present a case of a 47-year-old man, with deep venous thrombosis and spontaneous small bowel perforation. Since all possible known causes of small bowel perforation in this patient were excluded, a possible association with classic homocystinuria was considered. Homocysteine permanently degrades cysteine and lysine amino acid residues in proteins and, by this mechanism, may cause the connective-tissue weakness resulting in spontaneous pneumothorax or small bowel perforation. It could be hypothesized that connective-tissue weakness in homocystinuria is a result of homocysteine interference with recombinant human fibrillin-1 fragments or cross-linking of collagen through permanent degradation of disulfide bridges and lysine amino acid residues in proteins. DNA analysis showed three detectable mutations in the cystathionine beta-synthetase gene, 1278T:c.833T>C, and 2 new mutations, V372G:c.ll33T>G, and D520G:c.l558A>G in the alternatively spliced exon 15. [46]



Homocystinuria can cause pancreatitis.

Homocystinuria may result in thromboembolic complications.

Some authors speculate that inappropriate treatment might enhance CNS lesions of MAT I/III deficiency by causing a reversible vacuolating myelinopathy. Clinical symptoms (eg, mildly decreased appetite, sleepiness) and MRI findings (eg, abnormal T1 and T2 prolongations and reduced diffusion in the cerebral white matter) improved after discontinuation of therapy. [47]

Spontaneous pneumothorax can occur as a complication of pyridoxine-responsive homocystinuria. [48]

Legg-Calvé-Perthes disease, a previously unknown complication in homocystinuria, was seen in one of patients with the novel p.Trp323X mutation in Saudi Arabia. Some evidence suggests further support to the hypothesis of clotting abnormalities with vascular thrombosis. This may explain the occurrence of Legg-Calvé-Perthes disease in homocystinuria as a vascular thromboembolic consequence of the persistently elevated homocysteine, leading to vascular necrosis of the femoral head in this patient. [49]