Homocystinuria due to cystathionine beta-synthase deficiency

A rare metabolic disease of methionine catabolism characterized by accumulation of methionine and homocysteine with clinical involvement of the eye, skeletal system, vascular system and central nervous system (CNS).

Summary:
Epidemiology
The prevalence of the disease varies widely depending on ethnicity and the method of ascertainment, from 1/300,000 in historical clinical descriptions, to 1/1800 in Qatar (highest prevalence in the world), and an estimated 1/17,800 in Germany by molecular genetic screening of a normal population.
Clinical description
Patients exhibit a spectrum of progressively appearing clinical manifestations, ranging from asymptomatic to severe, with one or multiple organ systems involved. Symptoms essentially affect four types of organ: eyes (ectopia lentis), skeletal system (high stature, marfanoid morphotype, skeletal deformations, osteoporosis), vascular system (arterial or veinous thromboembolism), and CNS (developmental delay, autism spectrum disorders, psychiatric disorders). The phenotype and severity of the disease are essentially defined by the degree of response to vitamin B6, the cofactor of the cystathionine beta-synthase (CBS) enzyme.
Etiology
The disease is caused by mutations in the CBS gene (21q22.3) leading to the accumulation of homocysteine and methionine, which are toxic for the endothelium, and causes neurocognitive impairment. Cysteine deficiency probably plays a role in connective tissue abnormalities, including lens dislocation.
Diagnostic methods
The diagnosis is suspected in patients with increased plasma concentrations of total homocysteine (Hcyt) and methionine (Met), and confirmed by the identification of biallelic pathogenic variants in the CBS gene.
Differential diagnosis
The spectrum of differential diagnosis is broad. Clinically, severe forms of CBS deficiency share certain clinical features with Marfan syndrome (FBN1 gene), and lens dislocations are associated with a number of malformative syndromes. The differential diagnoses of hyperhomocysteinemia include some acquired pathologies such as severe chronic renal failure, vitamin B12 or folate deficiency (which can be caused by certain treatments such as methotrexate, metformin, nitrous oxide) and inborn errors of vitamin B12 or folate metabolism.
Antenatal diagnosis
Prenatal testing is possible if mutations have been identified in the index case.
Genetic counseling
The disease is autosomal recessive. At conception, each sib of heterozygous parents has a 25% risk of being affected.
Management and treatment
There are currently three recognized modalities of treatment. For patients who are pyridoxine responsive, treatment includes pyridoxine only in pharmacological doses (maximum 500 mg/day) in combination with folic acid and vitamin B12 supplements if necessary. In pyridoxine nonresponsive individuals, the recommended treatment is a strict methionine-restricted diet in combination with pyridoxine in partial responders. Betaine anhydrous is a methyl donor that can be used as an adjunct to the diet.
Prognosis
The consequences of untreated, or partially treated, CBS deficiency include thromboembolic events, intellectual disability, ocular and skeletal manifestations. Untreated CBS patients showed that the risk of complications increases with age. The prognosis of patients treated from the neonatal period is good, with virtually complete prevention of all abnormalities. In late-treated patients, therapy aims at preventing thromboembolic events and further escalation of the complications.

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Dr Juliette BOUCHEREAU | MetabERN* - Pr Manuel SCHIFF | MetabERN*

                                * European Reference Network


Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency is a metabolic disorder characterised by neurological manifestations.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Onset usually occurs during the first year of life with severe neurological signs, recurrent apnoea, microcephaly and convulsions. There is no megaloblastic anaemia. There are some forms with onset during childhood, adolescence, or adulthood beginning with mental regression, ataxia, and, most often, common psychiatric disorders of the schizophrenic type that may be linked to cerebrovascular accidents. Other symptoms such as subacute degeneration of the spinal chord have been reported.
Etiology
It is caused by mutations in the MTHFR gene (1p36.3). MTHFR deficiency results in abnormal intracellular folic acid metabolism and prevents reduction of 5-10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the remethylation of homocysteine into methionine. As a result, the disorder leads to methyltetrahydrofolate deficiency and consequently to homocystinuria and hypomethioninemia.
Diagnostic methods
Diagnosis may be suspected after analysis of amino acids by chromatography and measurements of total plasma homocysteine levels revealing highly elevated values of >100 micromol/L. Other biological findings include low levels of methyltetrahydrofolate in both the plasma and cerebrospinal fluid. Diagnosis is confirmed by measuring enzyme activity in lymphocytes or fibroblasts.
Differential diagnosis
The differential diagnosis should include other homocysteine remethylation disorders.
Antenatal diagnosis
Prenatal diagnosis is feasible through molecular or enzymatic analysis.
Genetic counseling
The disorder is transmitted as an autosomal recessive trait.
Management and treatment
Treatment of severe deficiency revolves around the administration of high-dose betaine, in combination with methionine, pyridoxine, vitamin B12 and folic or folinic acid supplements.
Prognosis
The prognosis is variable.

                            Last update:
                            January 2008

                            - Expert reviewer(s):
                            Pr Pascale DE LONLAY


Homocystinuria without methylmalonic aciduria is an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, encephalopathy and, sometimes, developmental delay, and associated with homocystinuria and hyperhomocysteinemia. There are three types of homocystinuria without methylmalonic aciduria; cblE, cblG and cblD-variant 1 (cblDv1).

Summary:
Epidemiology
Prevalence is unknown. To date, about 30 cases of cblE, about 38 cases of cblG, and 5 cases of cblDv1 have been reported.
Clinical description
Homocystinuria without methylmalonic aciduria manifests mainly in early childhood with failure to thrive, megaloblastic anemia, developmental delay, hypotonia, seizures and cerebral atrophy with white matter abnormalities. Some patients may have an acute expression in the first few months of life, with vomiting, poor feeding and lethargy. Patients develop homocystinuria, hyperhomocysteinemia and, sometimes, hypomethioninemia. A mild clinical phenotype and late-onset disease in the absence of neurological involvement have also been described for the cblE disorder. Presentation in adulthood with ataxia, dementia or psychosis has been observed in cblG.
Etiology
These disorders are caused by a functional deficiency of the cytoplasmic enzyme methionine synthase (MS), which catalyzes remethylation of homocysteine to form methionine. cblG is caused by mutations of the MTR gene (1q43), which encodes MS, while cblE is caused by mutations of the MTRR gene (5p15.3-15.2), which encodes methionine synthase reductase, an accessory protein required to maintain MS-bound cobalamin in its active form. The cblDv1 disorder results in decreased provision of the cobalamin coenzyme required for MS activity.
Diagnostic methods
Diagnosis is based on evidence of increased levels of homocystine in urine, and homocysteine or homocystine in plasma, and presence of megaloblastic anemia. Plasma methionine is frequently low. Genetic complementation analysis or identification of mutations in the MTR, MTRR or MMADHC genes can confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes multiple sclerosis, particularly for cblG. The forms of homocystinuria without methylmalonic aciduria can be distinguished on the basis of complementation analysis in cultured cells. In contrast to patients with classical homocystinuria due to cystathionine synthase deficiency, methionine is not elevated.
Antenatal diagnosis
Prenatal diagnosis is possible by identification of elevated homocysteine in amniotic fluid or by biochemical studies of cultured amniocytes. Mutation analysis is possible when the disease causing mutations have been identified in the index case. Treatment of the mother of an affected fetus with cobalamin during pregnancy has been carried out, and appears to have been successful in preventing development of disease.
Genetic counseling
All three types of methylcobalamin deficiency are inherited in an autosomal recessive manner.
Management and treatment
Treatment is based on daily intramuscular injections of 1 mg hydroxycobalamin (OHCbl), tapering the frequency of injections over time to one dose, one to three times a week. A few patients with cblG have required additional treatment with folates and betaine.
Prognosis
With treatment, biochemical parameters rapidly normalize and clinical symptoms of hypotonia, lethargy and impaired responsiveness improve within 24-48 hours. Hematologic parameters also improve. The improvement in psychomotor status is slow and often incomplete.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


A rare disorder of lipid metabolism characterized by severely elevated plasma total cholesterol, low-density lipoprotein (LDL) cholesterol levels, and subsequent premature formation of atherosclerotic plaques in the coronary arteries, proximal aorta, and other arteries, significantly increasing the risk of premature cardiovascular disease and death. Xanthomas of the skin and in tendons are also a hallmark of the disease. Lethality is high due to early complications, in particular myocardial infarction and aortic valvular disease.

Summary:
Epidemiology
The current prevalence estimate of homozygous familial hypercholesterolemia (FH) is approximately 1/315,000 (range 1/100,000-1,000,000) individuals, with a higher prevalence in founder populations (e.g. in the Middle East, Quebec and South Africa).
Clinical description
Classical clinical presentation is in childhood when xanthomas are first noted on extremities, trunk and in extensor tendons. Patients may also have corneal arcus, xanthelasmas, arterial bruits, cardiac ejection murmurs and diminished peripheral arterial pulses. A lipid profile demonstrates profoundly elevated levels of total and LDL cholesterol.
Etiology
The core molecular defect involves loss of function of the LDL receptor on hepatocytes due to bi-allelic pathogenic variants in the LDLR gene in 80-90% of cases. There are >3000 reported pathogenic variants in LDLR. Clinical severity varies in relation to the extent of functional impairment imparted by the particular variant. A similar phenotype can result from bi-allelic binding-defective variants in APOB which encodes apolipoprotein B, the ligand for the LDL receptor. About 1-2% of cases result from bi-allelic gain-of-function variants in PCSK9 which encodes proprotein convertase subtilisin kexin type 9. A true recessive phenotype results from bi-allelic loss-of-function variants in LDLRAP1 encoding the LDL receptor adaptor protein. Even rarer variants in other genes can sometimes produce a phenotype that resembles homozygous HF.
Diagnostic methods
Diagnosis is made based on clinical features, the degree of LDL cholesterol elevation, family history, plus DNA sequencing for a definitive diagnosis.
Differential diagnosis
Differential diagnosis includes severe heterozygous FH, sitosterolemia, lysosomal acid lipase deficiency.
Antenatal diagnosis
Prenatal diagnosis of homozygous FH is possible.
Genetic counseling
Transmission is semi-dominant when the causal gene is LDLR, APOB or PCSK9, meaning that heterozygous parents express an abnormal clinical and biochemical phenotype that is intermediate between a normal individual and a patient with homozygous FH. Parents either already know their own heterozygous status in advance, or sometimes are diagnosed retrospectively when a child is born with homozygous FH. Genetic counseling should be offered to at-risk couples: 25% of their children will have a normal lipid profile, 50% will have heterozygous FH which will require monitoring and sometimes pharmacotherapy starting at ages 8-10 years, and 25% will have homozygous FH requiring immediate attention. In true autosomal recessive FH due to bi-allelic loss-of-function variants in LDLRAP1, both parents are asymptomatic carriers of a disease-causing mutation with a 25% risk of having an affected child at each pregnancy.
Management and treatment
The mainstay of treatment is serial (i.e. weekly or bi-weekly) lipoprotein apheresis, since statins and other commonly used lipid-lowering medications are minimally effective. Inhibitors of proprotein convertase subtilisin kexin type 9 have a variable but typically modest effect on LDL cholesterol. A new biologic medication - evinacumab, which is an intravenously administered monoclonal antibody against angiopoietin like protein 3 - is an extremely effective treatment recently made available in many jurisdictions.
Prognosis
Life expectancy without treatment is reduced by three to five decades. With apheresis, patients now survive into their fifth and sixth decades of life, but still can develop clinical end points of severe premature atherosclerotic cardiovascular disease and aortic disease.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Dr Robert HEGELE


Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare congenital autosomal recessive disease, presenting in children and adolescents, and characterized by progressive scoliosis along with the absence of conjugate horizontal eye movements and associated with failure of the somatosensory and corticospinal neuronal tracts to decussate in the medulla.


Hot water reflex epilepsy is a rare neurologic disease characterized by the onset of generalized or focal seizures following immersion of the head in hot water, or with hot water being poured over the head. Primary generalized tonic-clonic seizures have been reported in rare cases.


House allergic alveolitis is a hypersensitivity pneumonitis (see this term) resulting from the inhalation of an antigen to which an individual has been previously sensitized in his/her domestic environment. House allergic alveolitis encompasses summer hypersensitivity pneumonitis, humidifier-induced lung diseases, hot tub lung and legionellosis (see this term).


A rare X-linked syndromic intellectual disability considered to be a severe variant of dyskeratosis congenita characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, progressive combined immune deficiency and aplastic anemia.

Summary:
Epidemiology
Hoyeraal-Hreidarsson syndrome (HHS) prevalence is unknown. The syndrome may be underdiagnosed due to high mortality rates.
Clinical description
The disease generally presents in early childhood and primarily affects males. Growth retardation is usually of prenatal onset. Other clinical manifestations include microcephaly, mucocutaneous lesions (hyperpigmentation, nail dystrophy, premalignant leukoplakia affecting oral and gastrointestinal mucosa), early onset bone marrow failure, immunodeficiency and pancytopenia. Cancer predisposition is also reported.
Etiology
HSS is caused by mutations in the DKC1 gene (Xq28), encoding the nucleolar protein dyskerin which interacts with the human telomerase RNA complex. Mutations in other genes (TERT, RTEL1 or TINF2, ACD, PARN) involved in telomere maintenance may be associated with this disorder.
Diagnostic methods
The disorder diagnosis is based on neuroimaging. Molecular genetic testing is needed to confirm diagnosis.
Differential diagnosis
Differential diagnoses include dyskeratosis congenita, Revesz-Debuse syndrome, Pseudo-TORCH syndrome, Fanconi anemia and Nijmegen breakage syndrome.
Antenatal diagnosis
Intrauterine growth failure and cerebellar hypoplasia can be detected by prenatal imaging (ultrasounds, MRI). If the familial mutation is known, prenatal genetic testing can be proposed.
Genetic counseling
HHS follows an X-linked recessive pattern of inheritance. The disorder is very rarely inherited as an autosomal recessive form.
Management and treatment
The aplastic anemia and immunodeficiency can be treated by bone marrow transplantation. Supportive treatment for gastrointestinal complications and infections is required.
Prognosis
The prognosis is poor as the disease follows a very severe course and premature death in childhood can occur due to bone marrow failure, but survival into adulthood is possible.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Eugen BOLTSHAUSER


A clinical subtype of HSD10 disease, a rare neurometabolic disorder. Affected boys may show lethargy, poor feeding and evidence of mitochondrial dysfunction in the newborn period, with subsequent mild developmental delay and abnormal muscle tone. Hallmark of the disease is progressive neurodegeneration and cardiomyopathy, which usually manifests between ages 6 months and 2 years with developmental regression, progressive visual and hearing loss, epilepsy and other neurological symptoms, and severe cardiomyopathy. Laboratory investigations show signs of mitochondrial dysfunction, and increased urinary excretion of specific isoleucine metabolites. The disease is often fatal around 2-4 years of age.


HSD10 disease, neonatal type is the most severe form of HSD10 disease, a rare neurometabolic disorder. It is characterized by severe metabolic/lactic acidosis in the neonatal period, little psychomotor development, seizures and severe progressive hypertrophic cardiomyopathy. Hepatic involvement and coagulopathy are rare. The disease is fatal within the first months of life.


HSD10 disease is a rare, life-threatening neurometabolic disease characterized by a progressive neurodegenerative course, epilepsy, retinopathy and progressive cardiomyopathy.

Summary:
Epidemiology
Prevalence is unknown. So far, fewer than 40 cases have been reported worldwide.
Clinical description
HSD10 disease is heterogeneous, including several clinical subtypes, and manifests by severe manifestations in males only; females are either asymptomatic or show non-progressive cognitive impairment ranging from learning difficulties to intellectual disability, as well as variable neurological abnormalities. HSD10 disease, infantile form is the classical presentation. Affected boys may show lethargy, poor feeding and evidence of mitochondrial dysfunction in the newborn period, with subsequent mild developmental delay and abnormal muscle tone. Hallmark of the disease is progressive neurodegeneration and cardiomyopathy, which usually manifests between ages 6 months and 2 years with loss of cognitive and motor skills, epilepsy, progressive visual impairment leading to blindness, and/or hearing loss. As neurodegeneration advances, patients develop progressive ataxia, choreoathetosis, and restlessness. The disease is generally fatal with death usually occurring between 2-4 years of age. Laboratory findings include lactic acidosis, hypoglycemia, hyperammonemia, and increased urinary excretion of specific organic acids. HSD10 disease, neonatal form is the most severe subtype. It is characterized by severe metabolic/lactic acidosis in the neonatal period, scarce neurological development, severe progressive cardiomyopathy and death within the first months of life. Other variants of HSD10 disease are less well defined and usually reflect attenuated forms. Affected individuals may have variable neurological and behavioral symptoms, intellectual disability which may be non-progressive, variable metabolic/non-neurological manifestations, or may be asymptomatic.
Etiology
HSD10 disease is mostly due to missense mutations in the HSD17B10 gene (Xp11.22), coding for 3-hydroxyacyl-CoA dehydrogenase type 2. This mitochondrial protein has at least dual function: (a) it is one of three proteins that constitute mitochondrial ribonuclease (RNase) P which is responsible for the cleavage of the mtDNA polycistronic transcript between mRNA and tRNA sequences; (b) the enzyme's dehydrogenase function is required for the breakdown of 2-methyl-3-hydroxybutyrate in isoleucine metabolism (MHBD) and may be active on other metabolites such as neuroactive steroids. Null mutations in the HSD17B10 gene are incompatible with life. The clinical manifestations of HSD10 disease are thought to be due to defective RNase P leading to mitochondrial dysfunction, whereas some metabolic abnormalities including the typical urinary organic acids findings are caused by impaired dehydrogenase function.
Diagnostic methods
Diagnosis is based on urinary organic acid analysis, as well as molecular studies. Elevated levels of isoleucine metabolites (in particular 3-hydroxy-2-methylbutyrate and tiglylglycine in conjunction with normal methylacetoacetate) are hallmark findings of the disease, although they reflect dehydrogenase and not RNase P dysfunction. Some individuals with HSD10 disease may show no biochemical abnormalities, whereas others with isolated dehydrogenase dysfunction may have little or no symptoms. Frequently there is biochemical or histological evidence of mitochondrial dysfunction such as rounded mitochondria with depleted cristae observed by microscopy. Diagnosis is confirmed by genetic analysis identifying a hypomorphic disease-causing mutation.
Differential diagnosis
Biochemical abnormalities may resemble beta-ketothiolase deficiency. Clinical abnormalities are similar in other disorders affecting mtDNA transcript processing, in particular ELAC2-associated disease (combined oxidative phosphorylation defect type 17).
Antenatal diagnosis
Prenatal diagnosis is possible by molecular analysis.
Genetic counseling
HSD10 disease follows an X-linked inheritance with variable manifestation in females. Genetic counseling should be proposed to at-risk families.
Management and treatment
At present, there is no effective treatment for the disease. A low-protein, high-energy dietary regimen with carnitine supplementation reduces the accumulation of isoleucine metabolites in blood and urine, but does not improve psychomotor deterioration. Due to its ability to interfere with mitochondrial energy metabolism, valproic acid should be avoided.
Prognosis
The prognosis is poor, especially for the neonatal and infantile forms of the disease. The prognosis for the attenuated or asymptomatic variants of the disease is currently unknown.

                            Last update:
                            October 2018

                            - Expert reviewer(s):
                            Pr Johannes ZSCHOCKE


HTRA1-related autosomal dominant cerebral small vessel disease

A rare genetic cerebral small vessel disease characterized by subcortical ischemic events associated with cognitive decline and gait disturbance with an age of onset typically in the sixth or seventh decade of life. Imaging reveals white matter hyperintensities, status cribrosus, lacunar infarcts, and sometimes microbleeds. Extra-neurological manifestations are absent.


Hughes-Stovin syndrome (HSS) is a life-threatening disorder, believed to be a cardiovascular clinical variant manifestation of Behçet's disease (BD; see this term). It is characterized by the association of multiple pulmonary artery aneurysms (PAAs) and peripheral venous thrombosis.

Summary:
Epidemiology
Prevalence is unknown but fewer than 30 cases have been reported in the literature since its first description in 1959 by Hughes and Stovin.
Clinical description
Patients (mostly men aged 12-40 years) generally present with the nonspecific signs of PAA (hemoptysis, cough, dyspnea, chest pain, and signs of pulmonary hypertension), following a history of peripheral venous thrombosis. Other associated signs may include fever and intracranial hypertension. Aneurysms usually involve the pulmonary arteries and the bronchial arteries resulting in subsequent hemoptysis. However, they can occur anywhere in systemic circulation. Recurrent phlebitis also commonly involves the large vessels, resulting in thrombus formation. In general, there is a predisposition for thrombus formation affecting the peripheral veins. Thrombosis of the vena cava and of the right atrium has also been described.
Etiology
The etiology of HSS is unknown; however, it is assumed that HSS is a form of vasculitis following a similar mechanism of pathogenesis to that thought to be involved in BD.
Diagnostic methods
Diagnosis of HSS is made on the basis of the clinical picture (association of venous thrombosis and PAAs in a young patient), patient history and imaging studies (chest radiographs, conventional angiography or helical computed tomography) for detection and evaluation of the PAAs. Histologic studies show destruction of the arterial wall and perivascular lymphomonocytic infiltration of capillaries and venules.
Differential diagnosis
The pulmonary manifestations of HSS and BD have been reported to be identical, but the two syndromes can be distinguished on the basis of the absence of mucocutaneous findings in HSS.
Management and treatment
Initial management of HSS often involves administration of corticosteroids, usually in combination with cytotoxic agents (intravenous cyclophosphamide followed by oral azathioprine) to stabilize the PAAs. Despite the presence of thrombosis, anticoagulants are contraindicated due to the risk of life-threatening PAA rupture. Surgical resection provides an effective treatment option for patients with unilateral or localized PAAs and less invasive approaches such as transcatheter embolization may be feasible in some cases.
Prognosis
As most patients with HSS are diagnosed late in the disease course, the syndrome is associated with significant mortality due to massive hemoptysis resulting from PAA rupture or systemic bronchial artery hypertrophy secondary to ischemia related to the pulmonary artery occlusion.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Pr David SAADOUN  - Pr Bertrand WECHSLER


A rare viral disease characterized by fever, malaise, lymphadenopathy, and a maculopapular exanthema spreading from the site of infection to other regions of the body. The skin lesions eventually dry out and may leave behind scars. The most relevant orthopox species for human disease after the eradication of the variola virus, which was responsible for smallpox, are the monkeypox virus and the cowpox virus. Infections with these viruses typically take a benign course.


A group of rare neurodegenerative diseases characterized by the accumulation of prions, abnormal variants of the cellular prion protein, primarily in brain tissue of affected individuals, as well as massive, rapid neuronal death, and an invariably fatal course. Human prion diseases most often occur sporadically but may also be of genetic origin or infectiously acquired. Irrespective of etiology, they are transmissible to other individuals.


An extremely rare familial bone deformity described only in Japanese patients to date. The deformity is bilateral in nearly half of patients (with bilateral involvement, the condition is symmetrical) and sometimes causes ulnar nerve palsy or cubitus varus.


Hunter-McAlpine craniosynostosis is characterised by craniosynostosis, intellectual deficit, short stature, facial dysmorphism (oval face with almond-shaped palpebral fissures, droopy eyelids and a small nose) and minor distal anomalies. It has been described in 10 patients. Transmission is autosomal dominant and the syndrome is associated with partial duplication of the long arm of chromosome 5 (5q35-5qter).


A rare, genetic, human prion disease characterized by adult-onset neurodegenerative manifestations associated with a movement disorder and psychiatric/behavioral disturbances. Patients typically present personality changes, aggressiveness, manias, anxiety and/or depression in conjunction with rapidly progressive cognitive decline (presenting with dysarthria, apraxia, aphasia, and eventually leading to dementia) as well as ataxia (manifesting with gait disturbances, unsteadiness, coordination problems), Parkinsonism, myoclonus, and/or chorea. Additional features may include generalized spasticity, seizures, urine incontinence and pyramidal abnormalities.


A rare severe neurodegenerative disorder that is considered one of the phenocopies of Huntington Disease (HD) affecting patients of African descent and characterized by a triad of movement (chorea, oculomotor, parkinsonism), psychiatric (prominently sadness, irritability and anxiety), and cognitive abnormalities (early cognitive decline and subcortical-like dementia).

Summary:
Epidemiology
Huntington disease-like 2 (HDL2) has been exclusively reported in patients of African descent. Although the prevalence and incidence are unknown it is the most common HD phenocopy in African populations with the highest frequency of HDL2 reported in Johannesburg, South Africa.
Clinical description
HDL2 usually presents in adulthood, but, as in Huntington disease (HD), the age of onset is inversely related to the size of the trinucleotide repeat expansion underlying the disorder. HDL2 manifests with chorea, and oculomotor abnormalities. This then progresses to parkinsonism with rigidity, bradykinesia and dystonia with dysphagia and weight loss finally dominating the clinical features. HDL2 has a heterogeneous neuropsychological profile characterized by early cognitive decline that progresses to a subcortical-like dementia in a heterogeneous fashion. The neuropsychiatric presentation is also variable but the most prominent symptoms include sadness, irritability and anxiety. Over the duration of the disease, the HDL2 and HD phenotypes are indistinguishable when comparing the cognitive, psychiatric and motor features. This makes HDL2 the disease which most closely resembles the HD phenotype.
Etiology
HDL2 is caused by expanded trinucleotide repeats of the JPH3 junctophilin 3 gene (16q24.3). Affected individuals have CTG/CAG repeat expansions of 41-60 triplets (normal range of repeats: 6-27).
Diagnostic methods
Diagnosis is based on analysis of the JPH3 gene in the presence of a clinical syndrome consistent with HDL2. Acanthocytosis was found in three cases but subsequently, this has not been found in other patients. Neuroimaging reveals bilateral striatal atrophy, in particular of the caudate nucleus. Generalized cortical atrophy may develop during the disease course. Neuropathologically, ubiquitin-immunoreactive intracellular neuronal inclusions are found in both HD and HDL2, however these only extend and become intranuclear inclusions in HD.
Differential diagnosis
Differential diagnoses include Huntington disease, Huntington-like disorders, McLeod neuroacanthocytosis syndrome, Parkinson disease, neuroferritinopathy, dentarubralpallidoluysian atrophy, chorea-acanthocytosis, benign hereditary chorea, spinocerebellar ataxia types 2,3,17, familial Creutzfeldt-Jakob disease, Wilson disease, aceruloplasminemia, pantothenate kinase-associated neurodegeneration, mitochondrial disorders, polycythemia rubra vera, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, familial Alzheimer, and Tourette syndrome.
Antenatal diagnosis
Routine methods for prenatal genetic testing can be applied.
Genetic counseling
HDL2 follows an autosomal dominant pattern of inheritance and genetic counseling is recommended. Anticipation has not been established yet in HDL2. Concerning pre-symptomatic testing, the same considerations as in Huntington disease should be followed: testing is usually requested or proposed when an individual has a parent who is known to have or is suspected of having a Huntington-like disease.
Management and treatment
No curative or disease-modifying treatments are currently available and management is symptomatic and is similar to that of HD.
Prognosis
HDL2 is a relentlessly progressive disorder with a poor prognosis.

                            Last update:
                            April 2022

                            - Expert reviewer(s):
                            Dr David ANDERSON  -  Aline FERREIRA-CORREIA


Huntington disease-like 3 is a rare Huntington disease-like syndrome characterized by childhood-onset progressive neurologic deterioration with pyramidal and extrapyramidal abnormalities, chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and (on brain MRI) progressive frontal cortical atrophy and bilateral caudate atrophy.


Huntington disease-like syndrome due to C9ORF72 expansions

A rare, genetic neurodegenerative disease characterized by movement disorders, including dystonia, chorea, myoclonus, tremor and rigidity. Associated features are also cognitive and memory impairment, early psychiatric disturbances and behavioral problems.


Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia.

Summary:
Epidemiology
Prevalence in the Caucasian population is estimated at 1/20, 000-1/10,000.
Clinical description
Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington disease, JHD; see this term). The classic sign is chorea that gradually spreads to all muscles. Other unwanted movements include tics, comparable to those seen in Tourette syndrome (see this term), but these are fairly rare. Cerebellar signs can appear sporadically, similar to the presence of hypo- and hypermetria. Dystonia (e.g. torticollis) can be the first motor sign in Huntington disease. Other less well-known, but prevalent and often debilitating features of HD include unintended weight loss, sleep- and circadian rhythm disturbances and autonomic nervous system dysfunction. Dysarthria and dysphagia become very prominent during the course of the disease. Talking and swallowing gradually become more problematic leading to choking at any time in some patients. All patients develop hypokinesia and rigidity leading to bradykinesia and severe akinesia. All psychomotor processes become severely impaired. Patients also experience cognitive decline. Psychiatric symptoms are very common in the early stage of the disease, often prior to onset of motor symptoms. The percentage of patients with psychiatric signs, such as low self-esteem, feelings of guilt, anxiety and apathy, varies between 33% and 76%. Suicide occurs more frequently in early symptomatic patients and also in premanifest gene carriers. The most risky periods for suicide are around the time of the gene test and when independence starts to diminish.
Etiology
HD is caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4 (4p16.3) in the huntingtin gene, HTT. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD, the repeat often exceeds 55.
Diagnostic methods
Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD and is confirmed by DNA determination Premanifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not.
Differential diagnosis
Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed.
Antenatal diagnosis
Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Pre-implantation diagnosis with in vitro fertilization is offered in several countries.
Genetic counseling
HD is transmitted in an autosomal dominant manner.
Management and treatment
To date, no cure is available. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required.
Prognosis
The progression of the disease leads to complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr R.A.C. [Raymund] ROOS


A rare genetic skin disease characterized by the triad of congenital scleroatrophy predominantly of the hands with sclerodactyly, palmoplantar keratoderma, and nail changes (consisting of hypoplasia, ridging, clubbing, and white discoloration). Additional features include palmar hypohidrosis and a high susceptibility to early-onset squamous cell carcinoma of affected skin areas.


Hurler syndrome is the most severe form of mucopolysaccharidosis type 1 (MPS1; see this term), a rare lysosomal storage disease, characterized by skeletal abnormalities, cognitive impairment, heart disease, respiratory problems, enlarged liver and spleen, characteristic facies and reduced life expectancy.

Summary:
Epidemiology
The prevalence of the Hurler subtype of MPS1 is estimated at 1/200,000 in Europe.
Clinical description
Patients present within the first year of life with musculoskeletal alterations including short stature, dysostosis multiplex, thoracic-lumbar kyphosis, progressive coarsening of the facial features (including large head with bulging frontal bones, depressed nasal bridge with broad nasal tip and anteverted nostrils, full cheeks and enlarged lips), cardiomyopathy and valvular abnormalities, neurosensorial hearing loss, enlarged tonsils and adenoids, and nasal secretion. Developmental delay is usually observed between 12 and 24 months of life and is primarily in the realm of speech with progressive cognitive and sensorial deterioration. Hydrocephaly can occur after the age of two. Diffuse corneal compromise leading to corneal opacity becomes detectable from three years of age onwards. Other manifestations include organomegaly, hernias and hirsutism.
Etiology
Hurler syndrome is caused by mutations in the IDUAgene (4p16.3) leading to a complete deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.
Diagnostic methods
Early diagnosis is difficult as the first clinical manifestations are not specific. Diagnosis is based on detection of increased urinary excretion of heparan and dermatan sulfate and confirmed by demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.
Differential diagnosis
Differential diagnoses include the milder form of mucopolysaccharidosis type 1, the Hurler-Scheie syndrome (see this term), although this form is associated with only slight cognitive impairment. Differential diagnoses also include mucopolysaccharidosis type 6 and type 2 and mucolipidosis type 2 (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling and testing should be offered to couples with a positive family history.
Management and treatment
Management is multidisciplinary. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for patients with Hurler syndrome under 2.5 years of age (and in selected patients over this age limit) as it can prolong survival, preserve neurocognition, and ameliorate some somatic features. HSCT should be performed early in the disease course, before developmental deterioration begins. Enzyme replacement therapy (ERT) with laronidase is recommended for all Hurler patients and is a lifelong therapy which alleviates non neurological symptoms. The early use of ERT has been shown to delay or even prevent the development of some of the clinical features of this condition. Additional management of Hurler syndrome is largely supportive, and includes surgical interventions (e.g. adenotonsillectomy, hernia repair, ventriculoperitoneal shunt, cardiac valve replacement, carpal tunnel release, spinal decompression); physical, occupational, and speech therapies; respiratory support (e.g., continuous positive pressure ventilation with oxygen supplementation); hearing aids; and medications for pain and gastrointestinal disturbances.
Prognosis
Patients often succumb to the condition in the first decade from respiratory and cardiac complications but ERT and HSCT can improve life expectancy. The timing of diagnosis, and therefore of treatment initiation, is an important factor for the success of both HSCT and laronidase.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Pr Michael BECK


Hurler-Scheie syndrome is the intermediate form of mucopolysaccharidosis type 1 (MPS1; see this term) between the two extremes Hurler syndrome and Scheie syndrome (see these terms); it is a rare lysosomal storage disease, characterized by skeletal deformities and a delay in motor development.

Summary:
Epidemiology
The prevalence of MPS I has been estimated at 1/100,000, with Hurler-Scheie syndrome accounting for 23% of cases or a prevalence of approximately 1/435,000.
Clinical description
Patients with Hurler-Scheie syndrome have normal or almost normal intelligence but exhibit various degrees of physical impairment. Patients present in the first years of life with musculoskeletal alterations to different degrees including short stature, multiple dysostosis, thoracic-lumbar kyphosis, progressive coarsening of the facial features to different degrees, cardiomyopathy and valvular abnormalities, neurosensorial hearing loss, enlarged tonsils and adenoids, and nasal secretion. Hydrocephaly can occur after the age of two. Corneal opacity is seen between two and four years of age and requires keratoplasty to restore sight. Other manifestations may include organomegaly, hernias and hirsutism.
Etiology
Hurler-Scheie syndrome is caused by mutations in the IDUA gene (4p16.3) leading to partial deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.
Diagnostic methods
Early diagnosis is difficult because the first clinical signs are not specific, but is very important to allow early treatment. Diagnosis is based on detection of increased urinary secretion of heparan and dermatan sulfate through 1,9-dimethylmethylene blue (DMB) test and glycosaminoglycan (GAG) electrophoresis, and demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.
Differential diagnosis
Differential diagnoses include the milder and more severe forms of mucopolysaccharidosis type 1 (Scheie syndrome and Hurler syndrome respectively), mucopolysaccharidosis typeVI and mucopolysaccharidosis type II (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is recommended.
Management and treatment
Management should be carried out by a multidisciplinary team and should include physiotherapy to maintain range of movement. Bone marrow or umbilical cord blood transplant has been successful and can preserve neurocognition, improve some aspects of the somatic disease and increase survival. However it is associated with many risks and most of the positive effects occur only if the procedure is performed in the first two years of life. The enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. Given through weekly infusions it leads to improvement of lung function and joint mobility. Enzyme replacement therapy (ERT) should be started at diagnosis and may be beneficial in patients awaiting hematopoietic stem cell transplantation (HSCT). Early treatment slows the progression of the disease. In individual patients with MPS1 of intermediate severity, HSCT may be considered if there is a suitable donor. There are however no data on the efficacy of HSCT in patients with this form of the disease.
Prognosis
Life expectancy for Hurler-Scheie syndrome may be reduced, with death occurring before adolescence due to serious cardiovascular and respiratory complications.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Pr Michael BECK


Hutchinson-Gilford progeria syndrome is a rare, fatal, autosomal dominant and premature aging disease, beginning in childhood and characterized by growth reduction, failure to thrive, a typical facial appearance (prominent forehead, protuberant eyes, thin nose with a beaked tip, thin lips, micrognathia and protruding ears) and distinct dermatologic features (generalized alopecia, aged-looking skin, sclerotic and dimpled skin over the abdomen and extremities, prominent cutaneous vasculature, dyspigmentation, nail hypoplasia and loss of subcutaneous fat).


A rare genetic disease characterized by infantile or childhood onset of abnormal growth of hyalinized fibrous tissue, giving rise to multiple cutaneous nodules and/or pearly papules predominantly affecting the scalp, ears, neck, face, hands, and feet. Involvement of other organs results in gingival hyperplasia, osteolytic bone lesions, and joint contractures. Some patients exhibit visceral involvement with intractable diarrhea, increased susceptibility to infections, and severe failure to thrive.


A rare form of mucopolysaccharidosis characterized by abnormal storage of hyaluronan in lysosomes due to deficiency of hyaluronidase 1. Clinical manifestations include knee and/or hip pain associated with swelling, diffuse joint involvement with proliferative synovitis and occurrence of multiple periarticular soft-tissue masses, short stature, and dysmorphic craniofacial features (such as flattened nasal bridge, bifid uvula, and cleft palate).


A rare, benign gestational trophoblastic disease that develops during pregnancy and is characterized by the abnormal fertilization, trophoblastic proliferation, and abnormal or absent embryo development. Hydatidiform moles can be either complete or partial.

Summary:
Epidemiology
In Europe, the condition occurs in approximately 1/1,000 pregnancies.
Clinical description
Complete moles are asymptomatic in 40% of cases. Most often, a mole is detected upon suspicion of miscarriage in the first trimester, with bleeding and pelvic pain. The clinical signs in the second trimester (vomiting, metrorrhagia, abnormal increase in the size of the uterus, and more rarely anemia or preeclampsia) are observed less often, due to early detection by ultrasound examination. Hyperthyroidism is exceptional. The clinical signs of a partial mole (metrorrhagia, vomiting, etc.) are rare. A mole is usually detected histologically on analysis of aspiration samples from a suspected miscarriage.
Etiology
The moles are caused by abnormal fertilization with an excess of paternal chromosome material. Complete moles result from fertilization of an enucleated ovocyte by one or two haploid spermatozoa. The karyotype is 46,XX (75% of cases) or 46,XY (25%). The mole is characterized by trophoblastic hyperplasia associated with generalized degeneration of chorionic villi and absence of an amniotic cavity and embryonal tissue. Partial moles result from fertilization of a normal ovocyte by two spermatozoa or one abnormal spermatozoon. This type of mole is characterized by focal trophoblastic hyperplasia, localized degeneration of chorionic villi and identifiable embryonal tissue. The karyotype is triploid in 99% of cases.
Diagnostic methods
Ultrasound of a complete mole may show a classic ''snow storm'' appearance (solid, hyperechoic areas of varying forms interspersed with liquid areas of various sizes) occupying the entire uterine cavity. Earlier ultrasound before 9-10 weeks of pregnancy can show a limited vesicular appearance of the placenta. Ultrasound of a partial mole may sometimes show focal vesicular change. Embryonic structures without an increase in uterine size are commonly found. Diagnosis is based on histological examination of the product of fertilization. Expert pathology review is often useful. When hydatidiform mole is suspected, determination of total chorionic gonadotropin (hCG) must be performed.
Differential diagnosis
Moles may be, but should not be, confused with gestational trophoblastic neoplasms or with prolonged retention of a ''classic'' spontaneous miscarriage.
Genetic counseling
Aside from very rare cases of recurrent moles in the same patient or in the same family (1% of cases, in which a mutation in the NLRP7, KHDC3L, MEI1 or C11orf80 genes have sometimes been found), genetic counseling is not required.
Management and treatment
Treatment of moles consists of suction evacuation of the uterine contents. Ultrasound guidance may be useful. Evacuation must be scheduled rapidly due to the risk of complications which increases with gestational age. Due to possible progression to gestational trophoblastic neoplasia (GTN), plasma hCG should be monitored until the levels normalize. Diagnosis of GTN warrants disease staging and appropriate chemotherapy.
Prognosis
After removal, the prognosis is excellent. The main risk is retention by incomplete aspiration (up 25% of cases) which may justify ultrasound follow-up in the weeks following aspiration. Retention (ultrasound image of more than 17 mm in anteroposterior diameter) may require a repeated aspiration in certain clinical circumstances. In about 15 % of cases of complete moles and in 0.5 to 5% of partial moles, the condition leads to gestational trophoblastic neoplasia in the weeks and months following mole evacuation.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Dr John COULTER


A rare cerebral malformation characterized by an almost or complete lack of cortex, specifically the cerebral hemispheres, with the cranium and meninges completely intact. In most cases, death occurs in utero or in the first weeks of life. Developmental delay, drug-resistant seizures, spastic diplegia, severe growth failure, deafness and blindness are typical.


A very rare Epstein-Barr virus-associated lymphoproliferative disorder characterized by a chronic, recurrent, vesiculopapular rash, which subsequently ulcerates and scars, located mainly on sun-exposed areas and which is associated with systemic manifestations, such as fever, weight loss, asthenia, facial edema, arthralgia, lymphadenopathy, hepatosplenomegaly and/or increased liver enzymes. Hypersensitivity to mosquito bites has been associated and an increased risk of developing systemic lymphoma has been reported.


A rare photodermatosis characterized by the development of pruritic or painful vesicles in a photodistributed pattern in response to sunlight exposure. The lesions heal with permanent varioliform scarring. Ocular involvement, deformities of ears and nose, or contractures of the fingers may occasionally be observed. Systemic signs and symptoms are absent. The condition typically occurs in childhood and regresses spontaneously in adolescence or young adulthood.


Hydrocephalus with stenosis of the aqueduct of Sylvius

A congenital, X-linked, clinical subtype of L1 syndrome characterized by severe hydrocephalus often of prenatal onset, adducted thumbs, spasticity (mostly evidenced by brisk tendon reflexes and extensor plantar responses) and moderate to severe intellectual disability. This subtype represents the severe end of the L1 syndrome spectrum and is associated with poor prognosis.


A rare, genetic, renal malformation syndrome characterized by nephrotic syndrome with focal segmental sclerosis associated with hydrocephalus, thin skin and blue sclerae. There have been no further descriptions in the literature since 1978.


Hydrocephalus-costovertebral dysplasia-Sprengel anomaly syndrome

A rare multiple congenital anomalies syndrome characterized principally by Sprengel anomaly (upward displacement of the scapula) and hydrocephaly. Other anomalies such as global developmental delay, psychosis, brachydactyly, and costovertebral dysplasia may also be present.


A rare form of syndromic obesity characterized by the association of congenital hydrocephalus, centripetal obesity, hypogonadism, intellectual deficit and short stature.

Summary:
Epidemiology
It has been described in two males from one family.
Genetic counseling
An X-linked recessive mode of inheritance was suggested.

                            Last update:
                            May 2009


A rare developmental defect during embryogenesis malformation syndrome characterized by congenital, non-communicating hydrocephalus, cerebellar agenesis and absence of the Luschka and Magendie foramina. Patients present with hypotonia, areflexia or hyporeflexia, seizures and/or cyanosis shortly after birth. The condition is fatal in the neonatal period. There have been no further descriptions in the literature since 1978.


Hydrocephaly-low insertion umbilicus syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by congenital hydrocephalus involving the lateral ventricles, low-set umbilicus, bilateral inguinal hernia, and mild facial dysmorphism (such as epicanthal folds, broad, flat nasal bridge, and small, bulbous nose). Additional reported manifestations include unilateral cryptorchidism, vesicoureteral reflux, and tetralogy of Fallot. There have been no further descriptions in the literature since 1993.


Hydrocephaly-tall stature-joint laxity syndrome is a multiple congenital anomalies syndrome described in two sisters and characterized by the presence of hydrocephalus (onset in infancy), tall stature, joint laxity, and thoracolumbar kyphosis. There have been no further descriptions in the literature since 1989.


Hydrolethalus (HLS) is a severe fetal malformation syndrome characterized by craniofacial dysmorphic features, central nervous system, cardiac, respiratory tract and limb abnormalities.

Summary:
Epidemiology
HLS is mostly present in families of Finnish descent, and annual incidence has been estimated at 1/20,000 in Finland. The mutation carrier frequency in the Western parts of Finland is 1.1% and 2.5% in Central and Eastern parts. The disease is much rarer in other geographical areas. The prevalence is not known.
Clinical description
Micrognathia and retrognathia, cleft lip/palate, a poorly formed nose, posteriorly rotated ears and deep-set eyes are the main craniofacial dysmorphic features observed in HLS. A midline defect in the occipital bone dorsal to the foramen magnum is present, resulting in a keyhole-shaped defect. Brain abnormalities include hydrocephaly and agenesis of midline structures such as corpus callosum, cerebellar vermis and septum pellucidum, leading to a wide opened fluid-filled space between lateral ventricles. HLS is also characterized by postaxial and preaxial polydactyly, respectively in the hands and feet, the latter being clubbed. About half of the patients have large septal cardiac defect. Abnormal lobulation of the lungs, stenosis of the airways (larynx, trachea or bronchus), and abnormal genitalia (including uterus duplex in females and ectopic testis in males) are also found.
Etiology
HLS is caused by mutations in HYLS1 (11q24.2) and KIF7 (15q26.1). All Finnish cases are homozygous for an A to G mutation in exon 6 of i>HYLS1 resulting in D211G substitution. The KIF7 mutation has been characterized in only one HLS family to date. Both genes code for ciliary or centriolar proteins that seem to be involved in early embryonic development of the midline.
Diagnostic methods
Ultrasound scan during pregnancy often reveals hydrocephaly and an abnormal structure of the brain. Cleft lip/palate, polydactyly, especially double big-toe with club-feet, and the heart defect may also be visible. Diagnosis of a newborn is based on physical examination, brain imaging autopsy, and/or genetic tests. Genetic testing of the affected child to verify the mutation helps prenatal diagnosis in future pregnancies.
Differential diagnosis
Differential diagnosis of HLS includes, in the absence of an index case, other midline multiple malformation syndromes like Pallister-Hall, pseudo-trisomy 13, oro-facio-digital type IV or VI, Joubert syndromes, as well as the severe form of Smith-Lemli-Opitz syndrome (see these terms).
Antenatal diagnosis
Antenatal diagnosis by ultrasonography and/or genetic testing is feasible at the end of the first trimester when a previous pregnancy was affected. HLS is associated with hydramnios (often severe) and preterm delivery when pregnancy evolves spontaneously.
Genetic counseling
As an autosomal recessive syndrome, HLS has a 25% recurrence risk after an affected pregnancy. Genetic counseling should be offered to affected families.
Management and treatment
There is no treatment for HLS.
Prognosis
Stillbirth or neonatal death is the rule, although rare cases with several months survival have been reported.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Riitta SALONEN-KAJANDER


Hydrops fetalis is a severe and challenging fetal condition usually defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities that manifests as edema, pleural and pericardial effusion and ascites. It is the end-stage of a wide variety of disorders. The cause may be immunologic (immune hydrops fetalis, IHF) or non immunologic (non-immune hydrops fetalis, NIHF), depending on the presence or absence of maternal antibodies against fetal red cell antigens (ABO incompatibility or rhesus (Rh) incompatibility).


Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

A rare mitochondrial disease characterized by prenatal complications including oligohydramnios, fetal growth restriction, hydrops, and anemia, followed by severe lactic acidosis, hyaline membrane disease, pulmonary hypertension, cardiac anomalies, liver dysfunction, urogenital abnormalities and progressive renal disease, seizures, thrombocytopenia, and sideroblastic anemia resulting in multisystem organ failure and death shortly after birth. Less severely affected patients surviving the neonatal period and showing sensorineural hearing loss and developmental delay have been reported.


A rare, genetic disorder of tryptophan metabolism characterized by massive urinary excretion of xanthurenic acid (XA), 3-hydroxykynurenine and kynurenine and increased XA concentration in plasma. The clinical phenotype is highly variable, ranging from asymptomatic or mild cases presentating with jaundice and vomiting, with subsequent normal development and growth, to more severe cases with manifestions which include intellectual disability, cerebellar ataxia, pellagra, progressive encephalopathy with muscular hypotonia, global developmental delay, stereotyped gestures and/or congenital deafness.


Hymenolepiasis is a cosmopolitan parasitosis caused by a hymenolepidid tapeworm infection, most commonly Hymenolepis nana, that is reported worldwide but particularly in tropical and subtropical countries and which is usually asymptomatic but in severe cases can also manifest with nausea, abdominal pain, anorexia, diarrhea and overall weakness.


A rare, genetic disorder of pyrimidine metabolism characterized by increased serum beta-alanine levels and severe phenotype including hypotonia, malaise, seizures, respiratory distress, lethargy and encephalopathy. Urinary excretion of beta-alanine, beta-amino-isobutyric acid, taurine, and gamma-amino-butyric acid is also elevated. There have been no further descriptions in the literature since 1994.


Hyper-IgM syndrome with susceptibility to opportunistic infections is a rare, genetic, non-severe combined immunodeficiency disorder characterized by normal or elevated IgM serum levels with low or absent IgG, IgA and IgE serum concentrations, which manifests with recurrent or severe bacterial infections and increased susceptibility to opportunistic infections (in particular, pneumonia due to P. jiroveci, but also chronic cryptosporidial, cryptococcal, cytomegalovirus and toxoplasma infections). Hematologic disorders (neutropenia, anemia, thrombocytopenia) are frequently associated. Immunologic findings reveal decreased numbers of CD27+ memory B cells and lack of germinal center formation.


Hyper-IgM syndrome without susceptibility to opportunistic infections is a rare, genetic, primary immunodeficiency due to a defect in adaptive immunity disorder characterized by normal or elevated IgM serum levels with low or absent IgG, IgA and IgE serum concentrations, which manifests with recurrent bacterial sinopulmonary and gastrointestinal infections, with frequent lymphoid hyperplasia (peripheral lymphadenopathy, tonsillar hypertrophy), with no increased susceptibility to opportunistic infections. Autoimmune manifestations (including immune cytopenias, arthritis and hepatitis) are occasionally associated. Immunologic findings reveal absent immunoglobulin class switch recombination and lack of defect of immunoglobulin somatic hypermutations in the presence of normal numbers of CD27+ memory B cells.


Hyperammonemia due to N-acetylglutamate synthase deficiency

A rare disorder of urea cycle metabolism causing a deficit of ammonia detoxification and arginine synthesis, and characterized by hyperammonemia of variable severity. Manifestations range from neonatal presentation of poor feeding, vomiting, lethargy, tachypnea, convulsions and coma to adult-onset headaches, hazy gastrointestinal symptoms, seizures, behavioral/psychiatric problems, confusion and lethargy.

Summary:
Epidemiology
To date, approximately 100 cases have been reported worldwide.
Clinical description
Onset occurs at any age... The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhea, poor feeding, seizures, hypotonia, global development delay, psychiatric symptoms and respiratory distress. The hyperammonemia might be severe and may lead to hyperammonemic coma.
Etiology
The primary disorder is caused by mutations in the NAGS gene (17q21.31), leading to a total or partial lack of activity in the encoded protein, N-acetylglutamate synthase (NAGS). NAGS is an allosteric activator of carbamylphosphate synthetase I (CPSI), the enzyme catalyzing the first step in ureagenesis. NAGS deficiency may also be secondary to certain organic acid disorders, defects in fatty acid metabolism or valproic acid treatment.
Diagnostic methods
Besides the hyperammonemia, diagnosis is evoked by a rise in glutamine coupled with decrease of citrulline/arginine and absence of urinary orotic acid. Confirmation by DNA analysis is mandatory. If the latter is not conclusive, enzymatic NAGS activity upon liver biopsy can help in the definite diagnosis.
Differential diagnosis
The principle differential diagnosis is carbamoyl phosphate synthetase 1 deficiency.
Genetic counseling
The primary disorder is transmitted as an autosomal recessive trait. The risk to siblings of inheriting the disease is 25%. Offspring of affected individuals are obligate carriers.
Management and treatment
Acute treatment of hyperammonemia of unknown etiology consists in high glucose perfusion (with withdrawal of proteins and lipids) and administration of ammonia scavengers (sodium benzoate and/or sodium phenylbutyrate), L-Arginine and N-carbamylglutamate. Once definite diagnosis of NAGS deficiency is established, daily administration of N-carbamylglutamate, a structural analogue of NAGS that activates CPSI, might be sufficient as a unique treatment without protein restriction.
Prognosis
In most cases, early treatment with N-carbamylglutamate (i.e. before the onset of permanent neurological sequelae) allows normal global development and an excellent quality of life without diet. Although the severity of the disorder is variable, the prognosis without treatment may be poor with neurological deficit and a potentially fatal outcome.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                            Dr Dries DOBBELAERE


Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

A rare, hereditary inborn error of metabolism characterized by an acute onset of encephalopathy in infancy or early childhood. Apart from these episodic acute events, the disorder shows a relatively benign course. Multiple metabolic abnormalities are present, including metabolic acidosis, respiratory alkalosis, hypoglycemia, increased serum lactate and alanine.


Hyperandrogenism due to cortisone reductase deficiency

A rare, genetic, endocrine disease characterized by defect in conversion of cortisone to active cortisol, resulting in ACTH-mediated excessive androgen release from adrenal glands. Premature adrenarche is typical with precocious pseudopuberty, proportionate tall stature and accelerated bone maturation in males, and hirsutism, oligoamenorrhea, central obesity and infertility in females. Imaging studies may indicate adrenal hyperplasia.


Hyperbiliverdinemia is a rare, genetic hepatic disease characterized by the presence of green coloration of the skin, urine, plasma and other body fluids (ascites, breastmilk) or parts (sclerae) due to increased serum levels of biliverdin in association with biliary obstruction and/or liver failure. Association with malnutrition, medication, and congenital biliary atresia has also been reported.


Hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency

A rare sterol metabolism disorder characterized by increased LDL cholesterol serum levels (which are resistant to treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors), hypertriglyceridemia, and decreased rate of bile acid excretion, resulting from cholesterol 7alpha-hydroxylase deficiency. Premature gallstone disease and/or premature coronary and peripheral vascular disease are frequently associated.


Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency

A rare congenital disorder of glycosylation characterized by cerebral and portal vein thrombosis, portal hypertension, macrocephaly, and persistent absence seizures. Additional reported features include mild to moderate global developmental delay and intellectual disability, as well as thrombocytopenia. Brain imaging may show variable stages of infarction and cerebral and cerebellar atrophy.


A rare, X-linked, syndromic intellectual disability disease characterized by neonatal hypertonia which evolves to hypotonia and an exaggerated startle response (to sudden visual, auditory or tactile stimuli), followed by the development of early-onset, frequently refractory, tonic or myoclonic seizures. Progressive epileptic encephalopathy, intellectual disability, and psychomotor development arrest, with subsequent decline, may be additionally associated.


Hypereosinophilic syndrome (HES) constitutes a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia and/or tissue eosinophilia associated with a wide range of clinical manifestations reflecting eosinophil-induced tissue/organ damage.

Summary:
Epidemiology
Prevalence is unknown. It frequently occurs in middle-aged patients, but may concern any age group.
Clinical description
Target-organ damage mediated by eosinophils is highly variable among patients, and consists of dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed by involvement of lungs (cough, breathlessness and wheezing) and digestive tract (nausea, vomiting, abdominal pain, diarrhea, ascites) in roughly 40%. Cardiac involvement is less frequent, but must be recognized early due to irreversible and life-threatening complications such as acute myocarditis, intraventricular thrombus, endomyocardial fibrosis and valve thickening and/or destruction. Constitutional symptoms of fever, myalgia and fatigue may occur. Other common complications include central or peripheral nervous system involvement, hepato- and/or splenomegaly, and coagulation disorders. Skin involvement is more frequently seen in lymphocytic HES and cardiac damage in FIP1L1-PDGFRA (F/P) fusion gene positive (+) chronic eosinophilic leukemia (CEL; see this term).
Etiology
Recent advances in underlying pathogenesis have established that what was once thought to be ''idiopathic'' HES may in some cases be due to either primitive involvement of myeloid cells (primary HES), essentially due to occurrence of an interstitial chromosomal deletion on 4q12 leading to creation of the F/P fusion gene (CEL), or to increased interleukin (IL)-5 production by a clonally expanded T cell population (lymphocytic variant HES), most frequently characterized by a CD3-CD4+ phenotype, or due to other reactive causes (secondary HES) such as helminthic infection. However, in roughly 3/4 of cases, pathogenesis remains unknown, now defining idiopathic HES. In those with unexplained persistent asymptomatic hypereosinophilia (HE), the provisional term HE of undetermined significance is given. A small subgroup of patients have HES that shows familial clustering (familial HES), presumably due to an as of yet unknown inherited gene.
Diagnostic methods
Diagnosis of HES relies on the observation of persistent and marked HE (> 1.5 × 109/L) and /or eosinophilic infiltration of tissue(s) responsible for target-organ damage. Once these criteria are fulfilled, further testing for eventual pathogenic classification is warranted using appropriate cytogenetic, phenotypic, and functional approaches. If underlying causes of HE have been excluded, the term idiopathic HES is appropriate.
Differential diagnosis
Differential diagnoses include drug allergies and parasitic infections, solid and hematological malignancies (i.e. chronic myeloid leukemia), eosinophilic granulomatosis with polyangiitis and human T cell lymphotropic virus infection (see these terms).
Management and treatment
Therapeutic management should be adjusted to disease severity and eventual detection of pathogenic variants. For F/P+ patients, imatinib has undisputedly become first line therapy. For others, corticosteroids are generally administered initially, followed by agents such as hydroxycarbamide, interferon-alpha, and imatinib, for corticosteroid-resistant cases, as well as for corticosteroid-sparing purposes. Recent data suggest that mepolizumab, an anti-IL-5 antibody that is currently available only in the setting of clinical trials or on a compassionate use basis for severe treatment-refractory disease, is an effective corticosteroid-sparing agent for F/P-negative patients.
Prognosis
Prognosis has improved significantly since defining HES, and currently depends on the development of irreversible endomyocardial fibrosis, as well as eventual malignant transformation of myeloid or lymphoid cells.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Pr Florence ROUFOSSE


A rare syndromic endocrine disease characterized by the association of hypergonadotropic hypogonadism and cataracts with onset during adolescence.


Hyperimmunoglobulinemia D with periodic fever

A rare autoinflammatory disease, and form of mevalonate kinase deficiency (MKD), characterized by periodic attacks of fever and a systemic inflammatory reaction (cervical lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgia and skin manifestations.

Summary:
Epidemiology
The prevalence is unknown but several hundred patients have been reported worldwide. This is unquestionably an under-representation as many patients remain undiagnosed. A founder mutation (p.V377I) may account for the large number of cases reported from the Netherlands.
Clinical description
The disease usually begins in the first year of life and rarely after 5 years of age, and involves recurrent attacks of fever with abdominal pain, vomiting and diarrhea. Joint involvement (arthralgia/arthritis), swollen lymph nodes, skin lesions (maculopapular rash, vasculitis with purpura or erythema nodosum), early-onset colitis, and headaches may also be observed. Aphthous ulcers may be found and affect the oral mucosa or more rarely the genital and rectal mucosa. Attacks usually last 3 to 7 days and recur every 2 to 8 weeks, but can vary between patients. Frequency of attacks is highest during childhood and usually decreases with age. Severity of attacks also appears to decrease with age. These attacks can occur spontaneously or can be triggered by vaccination, infection and emotional or physical stress. Growth and development is usually not affected, unlike in patients with more severe disease (mevalonic aciduria; MVA). Disease complications are rarely seen in hyperimmunoglobulinemia D with periodic fever (HIDS) patients, but can include AA-amyloidosis, hemophagocytosis, glomerulonephritis, abdominal adhesions, and very rarely joint contractures.
Etiology
HIDS is an inherited syndrome caused by mutations in the mevalonate kinase (MVK) gene (12q24). These MVK mutations lead to reduced, but not abolished enzyme activity. This in turn leads to impaired control of the production of inflammatory mediators, which in turn cause inflammatory (fever) attacks.
Diagnostic methods
Diagnosis is based on clinical manifestations of the disease along with genetic or biochemical evidence of MVK deficiency. Immunoglobulin A (IgA) and IgD levels may be elevated. However, measurement of IgD cannot confirm nor rule out the diagnosis of HIDS. During an attack, erythrocyte sedimentation rate (ESR) is increased, as well as serum C-reactive protein (CRP), IL-1, IL-6 and TNF-alpha levels. The diagnosis can be made when genetic testing reveals two pathogenic MVK mutations or when a decreased mevalonate kinase activity is found in leukocytes or fibroblasts. Measurement of urinary mevalonic acid might be useful to select patients for MVK gene-analysis or enzyme assay.
Differential diagnosis
Unlike HIDS, the severe form of MKD, MVA, results in nearly complete MVK deficiency. Other autoinflammatory disorders like familial Mediterranean fever (FMF), Tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS) and Muckle-Wells syndrome should be considered. In children, the clinical picture of HIDS can be indistinguishable from PFAPA syndrome.
Antenatal diagnosis
Prenatal diagnosis is theoretically possible, but is not usually done.
Genetic counseling
HIDS follows an autosomal recessive pattern of inheritance. When a couple has an affected child, there is a 25% recurrence risk in a next child. Genetic counselling is therefore recommended.
Management and treatment
There is no curative treatment for HIDS and currently no established standard therapy. Treatment with NSAIDs might relieve symptoms during attacks. Some patients have responded to high-dose prednisone, especially when given at the beginning of an attack. Interleukin-1 blockade with canakinumab or anakinra (IL-1 receptor antagonist) has also been successful in many cases. Etanercept has also been effective in some patients. Patients should be monitored closely for complications.
Prognosis
The prognosis in HIDS is good. Life expectancy is not shortened except in rare cases where severe infections or renal amyloidosis occur. Spontaneous complete disease remission is possible.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Dr Joost FRENKEL  - Dr Jerold JEYARATNAM


Hyperinsulinism due to HNF1A deficiency is a form of diazoxide-sensitive diffuse hyperinsulinism (DHI), characterized by transient or persistent hyperinsulinemic hypoglycemia (HH) in infancy that is responsive to diazoxide, evolving in to maturity-onset diabetes of the young subtype 1 (MODY-1; see this term) later in life.


A rare autosomal dominant form of familial hyperinsulinism characterized clinically by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C peptide ratio, and a variable age of onset.


Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency

A rare form of congenital diazoxide-sensitive diffuse hyperinsulinism due to short chain 3 hydroxylacyl-CoA dehydrogenase (SCHAD; HADH gene) deficiency and characterized by hyperinsulinemic hypoglycemia with seizures and reported to respond well to diazoxide. It presents with the classical manifestations of hyperinsulinemic hypoglycemia. Exceptional complications include sudden death, and in one case fulminant hepatic failure.


A rare form of congenital diazoxide-sensitive diffuse hyperinsulinism due to UCP2 deficiency and characterized by hypoglycemic episodes from the neonatal period, a good clinical response to diazoxide and a probable transient nature of the disease with spontaneous resolution.


A rare diffuse form of congenital hyperinsulinism characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia), chronic hyperammonemia and recurrent episodes of hypoglycemia induced by fasting and protein rich meals. Epilepsy and cognitive deficit, which are unrelated to hypoglycemia but possibly related to the chronic hyperammonemia, may also occur. This disorder is usually responsive to diazoxide treatment.


A rare muscle disorder characterized by episodic attacks of muscle weakness associated with an increase in serum potassium concentration.

Summary:
Epidemiology
The prevalence is estimated at around 1/200,000.
Clinical description
Attacks of muscle weakness generally begin during childhood (first decade). They vary in frequency, duration (a few minutes to hours) and severity (focal paresis to total paralysis). They generally involve the limb muscles and spare the facial and respiratory musculature. Episodes are triggered by rest after exercise, fasting and cold exposure. Other factors may include ingestion of potassium-rich food, stress, infection, glucocorticoids, anesthesia and pregnancy. Maintaining exercise alleviates symptoms. 12.5% of patients present with clinical moderate and permanent myotonia that frequently involves facial muscles (lid-lag sign, eye closure myotonia) while electrical myotonia can be demonstrated in at least 50% of patients on electromyography (EMG). When clinical and electrical myotonia are a feature of the disease, the condition is called hyperkalemic periodic paralysis with myotonia (see this term). Another particular form of the disease, periodica paramyotonia, shares features with paramyotonia congenita (see this term) i.e. weakness is preceded by muscle stiffness provoked by cold and exercise.
Etiology
HyperPP is a sodium muscle channelopathy due to point mutations (Thr704Met and Met1592Val mutations in 80% of cases) in the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. These mutations lead to defective inactivation of the channel.
Diagnostic methods
Diagnosis is based on clinical history, EMG and genetic tests. Hyperkalemia during attacks can be very mild and fugitive. Serum creatinine kinase (CK) levels can be slightly elevated. Classical EMG may record myotonic discharges and/or myopathic features. The prolonged exercise test is positive in 80% of cases (decrease of over 30% of the compound muscle actionpotential after exercise). Muscle biopsy may show non-specific results (muscle fibers atrophy with vacuoles).
Differential diagnosis
Differential diagnoses include secondary hyperPP caused by renal or endocrine diseases, other familial periodic paralyses such as hypokalemic or normokalemic PP (see these terms) and non dystrophic myotonias such as paramyotonia congenita (see this term).
Antenatal diagnosis
Prenatal diagnosis is theoretically possible if the disease-causing mutation in the family has been identified but is rarely performed because of the non life-threatening prognosis.
Genetic counseling
Transmission is autosomal dominant with almost complete penetrance but variable expression in severity within and between families. Genetic counseling should be offered to affected families informing them of the 50% risk the child of an affected parent has of inheriting the disease-causing mutation.
Management and treatment
Management of patients consists in medical therapy and avoidance of triggering factors. Gentle physical activity, ingestion of carbohydrate-rich drinks/snacks or inhaled salbutamol at the onset of attacks may abort them. Daily use of carbonic anhydrase inhibitors or thiazide diuretics helps in preventing attacks. Dietary advice includes regular meals (to prevent fasting) and avoidance of potassium-rich foods.
Prognosis
With age (generally after 40 years of age), the frequency of the episodes declines but some patients may develop chronic myopathy of variable severity that may cause permanent muscle weakness.

                            Last update:
                            October 2010

                            - Expert reviewer(s):
                            Dr Savine VICART


A rare skin disease characterized by usually asymptomatic, hyperkeratotic, reddish-brown papules primarily located on the lower extremities. Histological examination shows lamellar hyperkeratosis with abrupt peripheral basket-weave orthokeratosis, irregular acanthosis, and underlying lichenoid lymphocytic infiltrate. The condition may be sporadic or familial.


Hyperkeratosis-hyperpigmentation syndrome describes a very rare hyperpigmentation of the skin characterized by tiny hyperpigmented spots mainly on skin exposed to sunlight, together with mild punctate palmoplantar papular hyperkeratosis as a major feature. There have been no further descriptions in the literature since 1993.


Hyperlipidemia due to hepatic triacylglycerol lipase deficiency

A rare hyperalphalipoproteinemia characterized by elevated plasma cholesterol and triglyceride (TG) levels with a marked TG enrichment of low- and high-density lipoproteins (HDL), presence of circulating beta-very low density lipoproteins and elevated HDL cholesterol levels, in the presence of a very low, or undetectable, postheparin plasma hepatic lipase activity. Premature atherosclerosis and/or coronary heart disease may be associated.


A rare autosomal recessive disorder of lysine metabolism characterized by elevated levels of lysine in the cerebrospinal fluid and blood. Hyperlysinemia type I has been associated with a highly variable phenotype including seizures, hypotonia, and mild psychomotor delay, although isolated hyperlysinemia is probably a benign condition.


Hypermethioninemia due to glycine N-methyltransferase deficiency is a rare, genetic inborn error of metabolism characterized by a relatively benign clinical phenotype, with only mild to moderate hepatomegaly reported, in addition to laboratory studies revealing permanent, greatly increased hypermethioninemia, mild to moderate elevation of aminotransferases and highly elevated plasma S-adenosyl-methionine with normal S-adenosylhomocysteine and total homocysteine.


Hypermethioninemia encephalopathy due to adenosine kinase deficiency is a rare inborn error of metabolism disorder characterized by persistent hypermethioninemia with increased levels of S-adenosylmethionine and S-adenosylhomocysteine which manifests with encephalopathy, severe global developmental delay, mild to severe liver dysfunction, hypotonia and facial dysmorphism (most significant is frontal bossing, macrocephaly, hypertelorism and depressed nasal bridge). Epileptic seizures, hypoglycemia and/or cardiac defects (pulmonary stenosis, atrial and/or ventricular septal defect, coarctation of the aorta) may be associated. Clinical picture may range from neurological symptoms only to multi-organ involvement.


A rare, genetic disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or coagulation defects or other chronic liver dysfunction.

Summary:
Epidemiology
More than 100 cases have been reported in the literature to date. The prevalence in Northern Saskatchewan, Canada is especially high due to a founder effect and is estimated in this population at 1/1550 live births.
Clinical description
Age of onset can range from the neonatal period to adulthood and a wide phenotypic spectrum is noted. The neonatal presentation usually begins a few days after birth with lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Onset of symptoms (ranging from mild to severe) in the majority of patients occurs in infancy, childhood and adulthood with episodes of confusion, forgetfulness, hyperammonemic coma, intellectual disability, developmental delay, spastic paraplegia, cerebellar ataxia, learning difficulties, unexplained seizures, liver dysfunction (rarely failure) and coagulopathy with factor VII-, IX- and X-deficiencies. An aversion to protein-rich foods before diagnosis is often reported.
Etiology
The syndrome is due to mutations in the SLC25A15 gene (13q14) encoding the mitochondrial ornithine transporter 1 (ORNT1) which plays a role in ornithine transport across the mitochondrial membrane and consecutively in mitochondrial protein synthesis, metabolism of arginine and lysine, and synthesis of polyamines. Mutations in this protein disrupt the urea cycle, resulting in hyperornithinemia, hyperammonemia and homocitrullinuria. Patients with a complete ORNT1 deficiency present in the neonatal period with severe hyperammonemia whereas those with a partial deficiency present later, between infancy to adulthood.
Diagnostic methods
Diagnosis is based on clinical findings and specific metabolic abnormalities. Laboratory tests usually reveal increased urinary excretion of orotic acid, homocitrulline and uracil, and a rise in the levels of plasma polyamines, ornithine, glutamine, alanine, and liver transaminases. Plasma ammonia levels are elevated episodically or postprandially and plasma ornithine is chronically elevated and is a hallmark of the disease as is the presence of homocitrulline in urine. Molecular genetic testing confirms diagnosis.
Differential diagnosis
Differential diagnosis includes other urea cycle disorders as well as lysinuric protein intolerance. Hyperinsulinism-hyperammonemia syndrome, pyruvate carboxylase deficiency and secondary causes of hyperammonemia should also be considered.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles.
Genetic counseling
The pattern of inheritance is autosomal recessive; where both parents are unaffected carriers, there is a 25% risk of inheriting the disease.
Management and treatment
Treatment involves the adherence to a low protein diet along with citrulline or arginine supplementation. In resistant cases, sodium benzoate and/or sodium or glycerol phenylbutyrate may be necessary for control of plasma ammonia levels. Patients should be monitored during times of stress (e.g. pregnancy, surgery, intercurrent infections) and when taking certain medications (i.e. corticosteroids) as they can trigger an episode of hyperammonemia. Hyperammonemic coma is treated in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration), ammonia scavenger therapy implemented, catabolism reversed (with glucose and lipid infusions) and special care taken to reduce the risk of neurological damage.
Prognosis
With early diagnosis and proper adherence to treatment protocol the prognosis is better than for most other urea cycle defects. However, patients remain at risk for metabolic decompensation throughout life and irreversible neurological complications can occur if treatment is delayed.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Johannes HÄBERLE


Hyperostosis corticalis generalisata, also known as van Buchem disease, is a rare craniotubular hyperostosis characterized by hyperostosis of the skull, mandible, clavicles, ribs and diaphyses of the long bones, as well as the tubular bones of the hands and feet. Clinical manifestations include increased skull thickness with cranial nerve entrapment causing inconsistent cranial nerve palsies.


A rare primary bone dysplasia with increased bone density characterized by slowly progressive endosteal hyperostosis and osteosclerosis exclusively of the skull base and the calvaria, resulting in entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII. First symptoms often appear during the second decade of life and include disturbances in smell, vision, facial sensation and expression, hearing, and balance, as well as headaches due to increased ocular and intracranial pressure. After the fourth decade, radiological progression is minimal, although decreased intracranial volume can lead to death in severe cases.


A rare genetic disease characterized by synchronous or metachronous occurrence of primary hyperparathyroidism and ossifying fibroma of the maxilla and/or mandible, associated with an increased risk of parathyroid carcinoma. Occurrence of renal cysts or tumors, multiple uterine polyps, and thyroid tumors has also been reported.


Hyperphenylalaninemia due to DNAJC12 deficiency

A rare inborn error of metabolism characterized by increased serum phenylalanine, associated with variable neurological symptoms ranging from mild autistic features or hyperactivity to severe intellectual disability, dystonia, and parkinsonism. Laboratory analyses show normal tetrahydrobiopterin (BH4) metabolism and low levels of the CSF monoamine neurotransmitter metabolites homovanillic acid and 5-hydroxyindoleacetic acid.


Hyperphenylalaninemia due to tetrahydrobiopterin deficiency

A disorder of pterin metabolism characterized by tetrahydropterin (BH4) biosynthesis or recycling deficiencies, leading to central dopamine and serotonin deficiency, characterized by infantile-onset neurological disease of variable severity ranging from mild forms with minor neurological development to severe forms with hypotonia, developmental delay, complex movement disorder dominated by dystonia or dystonia parkinsonism.

Summary:
Epidemiology
The global prevalence of BH4 deficiencies remains unknown and great variance can be found among different countries. European newborn screening programs (NBS) reveal that the mean incidence of all hyperphenylalaninemias (HPA) is approximately 1/10,000, with BH4 deficiencies representing 1-2% of cases.
Clinical description
When left untreated, the deficiency leads to neurological symptoms starting shortly after birth. While the overall clinical phenotype of BH4Ds may overlap with numerous other disorders (e.g. cerebral palsy) certain clinical features may raise the clinical suspicion for a disorder of impaired neurotransmission (e.g. early onset parkinsonism, oculogyric crises, diurnal fluctuation of symptoms, or an unexplained cerebral palsy-like picture). It is important to note that patients may show a wide spectrum of clinical severity, ranging from asymptomatic individuals requiring no treatment to very severe disease courses.
Etiology
BH4Ds are caused by variants in the GCH1, PTS, SPR, QDPR and PCBD1 genes, which encode enzymes required for the BH4 biosynthesis or recycling. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). While variants in PTS, QDRP and PCBD1 cause a central dopamine and serotonin deficiency and HPA, patients with variants in GCH1 and SPR mostly have normal phenylalanine concentrations.
Diagnostic methods
BH4D should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. Since phe levels can be normal in GTP cyclohydrolase I and sepiapterin reductase deficiency, the occurrence of certain clinical features should raise the clinical suspicion for a disorder of impaired neurotransmission. The analysis of pterins in urine or dried blood spot (DBS) in patients and the analysis of dihydropteridine reductase (DHPR) enzyme activity in DBS has to follow in all patients with HPA on NBS. With suspicion clinical picture and missing HPA or the confirm the biochemical diagnosis by genetic evaluation of the respective gene is recommended. Depending on availability the measuring of the neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid can be helpful for the diagnosis or during follow-up of BH4Ds.
Differential diagnosis
BH4Ds should be differentiated from each other, namely hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I deficiency, pterin-4-alpha-carbinolamine dehydratase deficiency (PCDD) and 6-pyruvoyl-tetrahydropterin synthase deficiency. The differential diagnosis of BH4 deficiencies also includes classic phenylketonuria and hyperphenylalaninemia due to DNAJC12 deficiency.
Antenatal diagnosis
Prenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.
Genetic counseling
All BH4 deficiencies are autosomal recessive genetic disorders. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of sapropterin hydrochlorid) in disorders with HPA. In all disoders apart from PCDD, restoration of normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan) should be achieved. In case of insufficient clinical response or L-dopa-induced hyperkinesia long-acting dopamine agonists (e.g. pramipexole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors. PCDD patients receive sapropterin hydrdochlorid to control Phe levels.
Prognosis
Early treatment drastically improves, often even reconstitutes motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN*

                                * European Reference Network


A rare, congenital disorder of glycosylation-related bone disorder characterized by hypotonia, severe developmental delay, intellectual disability, seizures, increased serum alkaline phosphatase, short distal phalanges with hypoplastic nails, and dysmorphic facial features. In some cases, cleft palate, megacolon, anorectal malformations, and congenital heart defects have been reported.


A rare disorder of proline metabolism characterized biochemically by markedly elevated levels of proline in plasma and urine due to deficiency of proline oxidase. The reported clinical phenotype ranges from asymptomatic to variable neurologic and psychiatric manifestations (including global developmental delay, seizures, autistic features, and hyperactivity).


Hyperprolinemia type 2 is an autosomal recessive proline metabolism disorder due to pyroline-5-carboxylate dehydrogenase deficiency. The condition is often benign but clinical signs may include seizures, intellectual deficit and mild developmental delay.