Non-acquired combined pituitary hormone deficiency

Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies, due to mutations of pituitary transcription factors involved in pituitary ontogenesis.

Summary:
Epidemiology
Congenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy. The incidence of congenital hypopituitarism is estimated to be between 1:3000 and 1:4000 births.
Clinical description
Clinical presentation is variable, depending on the type and severity of deficiencies and on the age at diagnosis. If untreated, main symptoms include short stature, cognitive alterations or delayed puberty.
Etiology
Congenital hypopituitarism is due to mutations of several genes encoding pituitary transcription factors. Phenotype varies with the factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph and sometimes corticotroph deficiencies; pituitary hyper and hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph and gonadotroph deficiencies, limited head and neck rotation) and LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities).
Diagnostic methods
A diagnosis of combined pituitary hormone deficiency (CPHD) must be suspected when evident causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism. . .) have been ruled out. Clinical, biological and radiological work-up is very important to better determine which transcription factor should be screened. Confirmation is provided by direct sequencing of the transcription factor genes.
Genetic counseling
Type of transmission varies with the factor and the mutation involved (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal or recessive for POU1F1 and HESX1).
Management and treatment
An appropriate replacement of hormone deficiencies is required. Strict follow-up is necessary because patients develop new deficiencies (for example late onset corticotroph deficiency in patients with PROP1 mutations).
Prognosis
Prognosis is equivalent to patients without pituitary deficiencies if treatment is started immediately when diagnosis is confirmed, and if a specialized follow-up is performed.

                            Last update:
                            March 2008

                            - Expert reviewer(s):
                            Pr Thierry BRUE  - Dr Frédéric CASTINETTI


Non-acquired isolated growth hormone deficiency

A rare non-acquired pituitary hormone deficiency characterized by growth deficiency, delayed bone age, and short stature of variable severity and age of onset, and with variable response to treatment with recombinant human growth hormone, depending on the respective subtype of the disease. Hormone deficiency may be quantitative or qualitative in nature.


A rare genetic pituitary disease characterized by variable deficiency of all hormones produced in the anterior lobe of the pituitary gland. Clinical manifestations include hypothyroidism, hypogonadism, growth retardation and short stature, and secondary adrenal insufficiency. Age of onset is variable. Signs and symptoms usually develop gradually, and loss of the different hormones is often sequential.


Non-amyloid fibrillary glomerulopathy (non-amyloid FGP) is a rare cause of glomerulonephritis (GN) characterized by glomerular accumulation of non-amyloid fibrils in the mesangium and the glomerular (and rarely tubular) basement membrane, that mainly presents with renal insufficiency, micro-hematuria and nephrotic range proteinuria. Non-amyloid FGP and immunotactoid glomerulopathy (ITG, see this term) are often grouped together as pathogenetically related diseases.

Summary:
Epidemiology
Non-amyloid FGP is encountered in approximately 0.5 to 1.0% of native kidney biopsies. A peak of occurrence between the fifth and sixth decades of life is observed. Females are slightly more affected than men, and the disease mainly affects the Caucasian population.
Clinical description
The disease is characterized by subnephrotic or nephrotic range proteinuria, frequently associated with macro- or microscopic hematuria, hypertension and renal insufficiency. Patients present with edema, ascites, pleural effusion and an elevated risk of blood clots and infection.
Etiology
Non-amyloid FGP etiology is unknown. The disease is generally considered idiopathic but it may be associated with secondary causes such as a monoclonal (mainly immunoglobulin G4; IgG4) or oligoclonal (containing both IgG1 and IgG4) gammopathy, hepatitis B and C infections, autoimmune diseases and malignancies.
Diagnostic methods
The diagnosis of non-amyloid FGP is based on the biopsy specimen's absence of reactivity with Congo red and other agents typically used for the histochemical demonstration of amyloid tissues (i.e. Thioflavin T), as well as observation on light, fluorescence and electron microscopy. Crescents may be present, sometimes associated with crescentic fibrillary GN (FGN). Common histological patterns include those of a membranoproliferative GN, mesangial proliferative GN, diffuse proliferative GN with endocapillary exudation, sclerosing GN or membranous thickening of the capillary tufts. At the ultrastructural level, glomerular structures are infiltrated by amorphous acellular material composed of randomly arranged, non-branching fibrils, around twice the size of amyloid fibrils, and with no apparent lumen. Fibrillary deposits usually consist of polyclonal IgG and complement component 3. Granular electron-dense deposits may also be present and admixed among the accumulations of fibrils. Other laboratory features may include low serum albumin and an increase in creatinine and blood cholesterol.
Differential diagnosis
Differential diagnosis includes amyloidosis, ITG (see these terms) and the immune deposits seen in lupus nephritis (lupus membranous GN).
Management and treatment
Different therapeutic strategies have been reported for the disease, but treatment options are still not defined. The treatment of nephrotic syndrome is based on prednisone, alone in patients with preserved renal function, or associated with cyclophosphamide in cases with crescentic FGN. Clinical trial data demonstrated the association of rituximab with a decrease of proteinuria and a possible role of rituximab in preventing or slowing the progression of renal disease in patients with preserved renal function has been hypothesized.
Prognosis
Despite treatment, non-amyloid FGP prognosis remains poor, with progression to end-stage renal failure occurring within a few months to a few years in about half of patients. Fibril deposition may recur in transplanted allografts but the recurrent disease has a relatively benign course.

                            Last update:
                            March 2016

                            - Expert reviewer(s):
                            Dr Laure Hélène NOEL


Non-amyloid monoclonal immunoglobulin deposition disease

A rare, secondary glomerular disease characterized by proteinuria, dysproteinemias, nephrotic syndrome, and nodular glomerulopathy leading to renal failure, with or without extra-renal manifestations. The renal biopsy shows typical deposits of monoclonal immunoglobulins that do not show a fibrillar organization and are negative for Congo red staining. Associated signs and symptoms depend on the involvement of other organs, liver, heart, nerve fibers, gastrointestinal tract, or skin.


Non-distal monosomy 10q is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 10, with a highly variable phenotype principally characterized by developmental delays (usually of language and speech), variable cognitive impairment and neurobehavioral abnormalities such as autism spectrum disorders and attention deficit disorder. Macrocephaly and mild dysmorphic features may by associated. Overlap with other syndromes, such as Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and juvenile polyposis syndrome has been reported.


A partial autosomal monosomy characterized by variable combination of developmental delay, intellectual disability, ectodermal, genitourinary and minor cardiac anomalies, and specific dysmorphic features (prominent forehead and low-set ears). Specific combination depends on the size and breakpoints of deleted regions.


Non-distal trisomy 10q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 10, characterized by mild to moderate developmental delay, postnatal growth retardation, central hypotonia, craniofacial dysmorphism (incl. microcephaly, prominent forehead, flat, thick ear helices, deep-set, small eyes, epicanthus, upturned nose, bow-shaped mouth, highly arched palate, micrognathia), ocular anomalies (e.g. iris coloboma, retinal dysplasia, strabismus), long, slender limbs and skeletal and digital anomalies (scoliosis, poly/syndactyly). Additional features reported include cardiac defects (e.g. septal ventricular defect), anal atresia, and cryptorchidism.


Non-distal trisomy 13q is a rare chromosomal anomaly disorder, resulting from the partial duplication of the proximal long arm of chromosome 13, with a highly variable phenotype principally characterized by increased polymorphonuclear leucocyte projections and persistence of fetal hemoglobin, as well as growth and developmental delay and craniofacial dysmorphism (incl. microcephaly, depressed nasal bridge, stubby nose, low-set, malformed ears, cleft lip/palate, micrognathia). Strabismus, clinodactyly and undescended testes in males may also be associated.


Non-distal trisomy 9q is a rare chromosomal anomaly syndrome, resulting from the partial trisomy of the long arm of chromosome 9, with a highly variable phenotype principally characterized by developmental delay, short stature, intellectual disability, and craniofacial dysmorphism (e.g. microcephaly, broad forehead, low set ears, epicanthus, prominent nose, and retrognathia). Cardiac, ocular, thyroid and esophagus defects, as well as central nervous system and behavioral/psychiatric abnormalities, have also been reported.


Non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome

Noneruption of teeth - maxillary hypoplasia - genu valgum is an extremely rare syndrome that is characterized by multiple unerupted permanent teeth, hypoplasia of the alveolar process and of the maxillo-zygomatic region, severe genu valgum and deformed ears.


A rare neuroendocrine tumor arising from neural crest-derived paraganglion cells (most often in the para-aortic region at the level of renal hilia, organ of Zuckerkandl, thoracic paraspinal region, bladder, and carotid body) not associated with catecholamine secretion. These tumors are usually clinically silent and symptoms, if present, are nonspecific and depend on the location of the tumor. Association with certain hereditary cancer-predisposing syndromes, such as multiple endocrine neoplasia, neurofibromatosis type 1 or von Hippel lindau syndrome, may be observed.


A rare pituitary tumor originating from normally hormone-producing cells of the adenohypophysis, characterized by a sellar or extrasellar mass manifesting with clinical signs secondary to mass effect, but without evidence for hormonal hypersecretion. Typical manifestations are visual disturbances, headaches, cranial nerve dysfunction, and hypopituitarism but the mass may also be discovered incidentally.

Summary:
Epidemiology
Prevalence of pituitary adenoma in the general population ranges between 1/1000 - 1,300; non-functioning pituitary adenoma (NFPA) accounts for 15-30% of these. Annual incidence is estimated at 1/100,000 worldwide.
Clinical description
NFPA is most often diagnosed in middle-aged adults (average age 50-60 years). The vast majority of NFPAs are revealed by mass effects on anatomic structures in the vicinity of the pituitary (headache, optic chiasm compression) and/or on pituitary hormonal function, leading to hypopituitarism. Pituitary stalk compression can also produce hyperprolactinemia causing amenorrhea and galactorrhea. Pituitary apoplexy may be the presenting feature of NFPA, with severe headaches of sudden onset, meningismus, a variably depressed sensorium, and visual disturbances. However, an increasing proportion of pituitary tumors are detected incidentally on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain performed for unrelated reasons. Very rarely, gonadotropin hypersecretion can stimulate the gonads: macro-orchidism has been reported in males and an ovarian hyperstimulation syndrome in premenopausal women with FSH (Follicle Stimulating Hormone)-secreting tumors.
Etiology
NFPAs are sporadic in the vast majority. The gene aryl hydrocarbon receptor interacting protein, AIP (11q13.3), has been identified as a susceptibility factor, particularly in cases of familial isolated pituitary adenomas (FIPA) or when NFPA begins in childhood or adolescence. NFPA may also be part of multiple endocrine neoplasia syndrome such as MEN1 (gene MEN1, 11q13).
Diagnostic methods
Assessment of tumor volume and extension is based on imaging studies (MRI). Potential visual problems related to compression of optic pathways are diagnosed by evaluation of visual acuity, visual fields and occasionally optic coherence tomography (OCT). Hypopituitarism is diagnosed by measurement of the various pituitary hormones and hormones from the target glands (cortisol, thyroid hormones, etc.). Dynamic tests may be necessary, particularly for assessment of corticotropic axis. Hyperprolactinemia may be found related to pituitary stalk compression and disinhibition of the dopaminergic tone that normally acts at the level of pituitary lactotrophs. Gonadotropins serum levels, particularly FSH may be increased arguing for the gonadotroph nature of the NFPA.
Differential diagnosis
In case of hyperprolactinemia, prolactin (PRL) serum levels are always below 150-200 ng/ml in patients with NFPAs. This distinguishes them from macroprolactinomas, which are associated with much higher PRL levels proportional to tumor size. Other differential diagnoses include other tumors of the sellar region (meningiomas, craniopharyngiomas, metastasis, etc.) and inflammatory process (hypophysitis, sarcoidosis, histiocytosis).
Management and treatment
Treatment is aimed at correcting (or preventing) tumor compression by excising the disease-causing lesion. Transsphenoidal surgery is often the first-line treatment. If a tumor remnant persists (a frequent situation in patients with large and often invasive adenomas), watchful waiting is preferred to routine radiotherapy, as long as the tumor residue does not grow. NFPA can sometimes recur even after complete resection. Postoperative irradiation is only considered in case of residual tumor growth or relapse. NFPA discovered incidentally may require a different approach, especially when they are small and/or remote from the optic pathways. If hypopituitarism persists, adequate hormone replacement is indicated.
Prognosis
A small excess mortality rate in women and in patients with a young age at diagnosis has been reported.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Philippe CHANSON


A disorder that is characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain.

Summary:
Epidemiology
Prevalence is estimated at 1/100,000.
Clinical description
Two forms have been described: hereditary angioedema (HAE; 90% of cases) usually occurring in childhood or adolescence, and acquired angioedema (AAE) usually occurring after 50 years of age (see these terms). Patients present with white, circumscribed nonpruritic edemas that remain for a period of 48 to 72 hours and recur with variable frequency. The edemas may involve the digestive tract resulting in a clinical picture similar to that seen in intestinal occlusion syndrome, sometimes associated with ascites and hypovolemic shock. Laryngeal edema can be life-threatening with a risk of death of 25% in the absence of appropriate treatment. Dental procedures are a triggering factor for laryngeal edema. Edemas of the face are a risk factor for laryngeal involvement.
Etiology
Angioedema can be caused by quantitative or functional defects of the plasma protease C1 inhibitor (C1-INH encoded by the SERPING1 gene; 11q12-q13-1) or by gain-of-function mutations of coagulation factor 12 (Hageman factor; F12; 5q33-qter). Angioedema is triggered by bradykinin excess. Transmission of HAE is autosomal dominant and AAE may be associated with a lymphoproliferative syndrome or the presence of anti-C1-INH autoantibodies. It may also be a rare side effect of renin-angiotensin-aldosterone system blockers (RAAS-blocker-induced angioedema; see this term).
Diagnostic methods
Diagnosis is based on clinical findings, measurement of C4 concentrations and on quantitative and functional analysis of C1-INH. C1q levels are low in patients with AAE but are normal in patients with HAE.
Differential diagnosis
Differential diagnoses include intestinal occlusion syndrome and histamine-induced angioedema (of allergenic or nonallergenic origin) generally associated with urticaria.
Management and treatment
Management of acute attack includes administration of subcutaneous icatibant or intravenous administration of C1-INH concentrate. Tranexamic acid and danazol can be administered for long term prophylaxis. For the acquired form, management aims to treat the associated disease.
Prognosis
With proper diagnosis and treatment, prognosis for patients with HAE is good. The prognosis of AAE depends on the underlying disorder.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


A heterogeneous group of malignant tumors of the lymphoid system.


A rare gastroesophageal disease characterized by diffusely enlarged gastric folds, excessive mucus secretion, normal serum protein and gastric TGF-alpha levels. Patients typically present anemia, abdominal pain not related to eating or bowel habits and absence of peripheral edema.


Non-immune hydrops fetalis (NIHF), a form of HF, is a severe fetal condition defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities, and is the end-stage of a wide variety of disorders.

Summary:
Epidemiology
The prevalence of NIHF is unknown as it is difficult to obtain when many cases are not diagnosed before intrauterine death or may spontaneously resolve antenatally. Currently, NIHF constitutes up to 90% of all HF cases.
Clinical description
NIHF presents during the gestational period and manifests as pleural and pericardial effusion, ascites and subcutaneous edema in the fetus. Decreased fetal movements may be noted prior to diagnosis. Often associated are polyhydramnios, fetal tachycardia, and antenatal hemorrhage. Mothers may develop massive anasarca, hypertension, and proteinuria (mirror syndrome). Death of fetus is usually due to heart failure and hypoxia. Surviving newborns may present with respiratory distress, pale skin, severe edema (mainly of abdomen) and enlarged liver and spleen. There is sometimes a risk of death of the mother.
Etiology
NIHF is the result of an increase in interstitial fluid production or, in turn, of an obstruction of lymphatic return. Causes can be: cardiovascular (21.7%; Ebstein malformation, tetralogy of Fallot), hematologic (10.4%; Hb Bart's HF), chromosomal (13.4%; Turner syndrome) and more rarely: infectious (TORCHES-CLAP (Toxoplasma gondii; Rubella virus; Cytomegalovirus; Herpes simplex virus; Enterovirus; Syphilis; Chickenpox virus; Lyme disease; Aids; Parvovirus B19)), syndromic (Costello syndrome, Meckel syndrome, thanatophoric dysplasia) or idiopathic. Other causes can include lymphatic dysplasia, inborn errors of metabolism (transaldolase deficiency, mucopolysaccharidosis, Niemann-Pick disease type C, GM1 gangliosidosis type 1), thoracic and urinary tract malformations, cardiac /extra thoracic tumors, and congenital diaphragmatic hernia.
Diagnostic methods
Decreased fetal movements, polyhydramnios, and maternal pre-eclampsia may lead one to suspect NIHF. Diagnosis is usually by ultrasound (showing fluid accumulations) during the 2nd to 3rd trimester of gestation. Having a placenta thickness of 5 mm or more, especially with a ''ground glass'' appearance on ultrasound may also be indicative of NIHF. Maternal laboratory tests such as blood typing, antibody screens for TORCHES-CLAP, hemoglobin electrophoresis, maternal anti-SSA/SSB antibodies as well as Kleihauer-Betke and alpha-fetoprotein tests, can also aid in the diagnosis of NIHF.
Differential diagnosis
The many disorders associated with HF are differential diagnoses such as neonatal hemochromatosis, twin-to-twin transfusion syndrome, congestive heart failure, hepatitis B, hypercalcemia, hypernatremia, hypothrombinemia, hypothyroidism and diabetes (in mother). Conditions that mimic full-blown HF include obstructed or mature bowel, fetal abdominal cysts and an obstructed urinary system.
Antenatal diagnosis
Prenatal diagnosis is by ultrasound.
Genetic counseling
If NIHF is due to a genetic disorder, counseling can be offered in regards to that disease.
Management and treatment
Treatment depends on the cause. Intrauterine treatment can involve thoraco-amniotic drainage, antiarrhythmic drugs (digoxin, sotalol, propranolol) and blood transfusion when anemia is present. In many cases, especially those caused by chromosomal abnormalities, the mother may choose to terminate the pregnancy. If the fetus comes to term it should be delivered at a tertiary care center where the neonate can receive intensive resuscitation procedures in the delivery room, intensive neonatal care, high frequency ventilation, parenteral nutrition, medications for the kidneys and removal of excessive fluid from around the lungs and abdomen as necessary.
Prognosis
In most cases, prognosis is poor with a perinatal mortality rate ranging from 55-98%, but it is dependent on etiology.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Dr Carlo BELLINI


Non-insulinoma pancreatogenous hypoglycemia syndrome

A rare familial hyperinsulinism characterized by postprandial hyperinsulinemic hypoglycemia, negative 72-hour fasts, negative preoperative localization studies for insulinoma, and positive selective arterial calcium infusion tests. Histopathological analysis reveals diffuse islet hyperplasia with increased number and size of islet cells.


Non-involuting congenital hemangiomas (NICH) are a distinctive type of large congenital hemangioma that are fully formed in utero and differ from rapidly involuting congenital hemangiomas (RICH; see this term) mainly because they do not undergo a postnatal involuting phase.

Summary:
Epidemiology
Prevalence is unknown but the lesions appear to be rare.
Clinical description
NICH have long been confused with infantile immature hemangiomas in their involuting stage, however, NICH are now clearly distinguished on the basis of their clinical features, course, pathology and immunophenotype. NICH are generally less expansive at birth than RICH. They are flat or slightly bossed, round or oval, and are usually solitary. The outer area appears white. The centre varies from pinkish with minor telangiectasia, to deep purple with closely packed thin telangiectasia. NICH are mainly located on the head or neck (43% of cases), and limbs (38% of cases). NICH will not regress: they persist indefinitely with proportionate growth as the child becomes older.
Etiology
The etiology is unknown.
Diagnostic methods
At birth, color Doppler ultrasound reveals a fast-flow lesion and minor arteriovenous fistulas are occasionally detected. However, in some patients, NICH may increase equatorial venous drainage and arteriovenous fistulas may become obvious on examination by color Doppler ultrasound. On MRI, NICH show isointensity on T1-weighted images, hyperintensity on T2-weighted images, and intensive enhancement after intravenous gadolinium administration. However, all of these findings are similar to those seen in infantile hemangiomas (IH). Immunohistochemical studies can be used to differentiate NICH and IH, as in contrast to IH, the endothelial cells of NICH lack immunoreactivity for GLUT-1. Histopathologic studies reveal that NICH consist of rather large lobules made of small capillaries lined by endothelial cells with hobnailed nuclei. Lobules are separated by dense fibrous tissue. Elongated thin-walled vessels and a large distorted channel are present in their center. Extralobular vessels are large. Calcifications may be seen. Numerous alpha-actin-positive cells are observed in the lobules.
Differential diagnosis
For lesions of intermediate size it may be difficult to distinguish between NICH and RICH at birth. NICH must also be differentiated from the congenital, single plaque-type of tufted angioma and from a kaposiform hemangioendothelioma (see these terms), and a biopsy may be indicated.
Antenatal diagnosis
In contrast to RICH, prenatal color Doppler ultrasound follow-up during pregnancy rarely leads to detection of NICH. NICH are not associated with any specific risks during delivery.
Genetic counseling
Genetic counseling should not be recommended as this rare tumor is sporadic. NICH never involute.
Management and treatment
The only therapeutic option is surgical excision and plastic reconstruction when there is cosmetic impairment. Neither arterial embolization alone, nor pulsed dye laser photocoagulation are of benefit. Performed 24 hours before excision, arterial embolization prevents excess intra-operative bleeding in some large NICH with arteriovenous fistulas detected by Doppler ultrasound.
Prognosis
Prognosis is good: NICH is a benign lesion, only impairing the cosmetic aspect of the skin. No severe complications have been reported.

                            Last update:
                            September 2008

                            - Expert reviewer(s):
                            Dr Odile ENJOLRAS  - Pr Marie-Paule VAZQUEZ


Non-progressive cerebellar ataxia with intellectual disability

A rare subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1) characterized by the onset in infancy of cerebellar ataxia, neonatal hypotonia (in some), mild developmental delay and, in later life, intellectual disability. Less common features include dysarthria, dysmetria and dysmorphic facial features (long face, bulbous nose long philtrum, thick lower lip and pointed chin).


Non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy

A rare mitochondrial disease characterized by a distinctive MRI pattern of cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. The clinical picture varies widely between acute neurometabolic decompensation in infancy with loss of developmental milestones, seizures, and pyramidal signs rapidly evolving into spastic tetraparesis, to subtle neurological symptoms presenting in adolescence. The disease course tends to stabilize over time in most patients, and marked recovery of milestones may be observed.


Non-recovering obstetric brachial plexus lesion

A rare acquired peripheral neuropathy characterized by paresis of the supraspinatus, infraspinatus, deltoid, and biceps muscles (in C5-C6 injury), wrist and finger extensor muscles (C7 injury), or impaired hand function (C8-Th1 injury) on the affected side due to a traction lesion of the brachial plexus during delivery. The upper trunk of the brachial plexus is most commonly affected, while isolated injury to the lower trunk is very rare. Potential sequelae of brachial plexus injury are muscle atrophy, pain, sensory deficits, and secondary deformities.


Non-rhizomelic chondrodysplasia punctata is a form of chondrodysplasia punctata (see this term), a group of diseases in which the common characteristic is bone calcifications near joints from birth. Non-rhizomelic chondrodysplasia punctata is not an entity in itself but covers several diseases with variable clinical findings and modes of transmission.

Summary:
Epidemiology
The overall prevalence of these diseases as a group is unknown.
Clinical description
X-linked dominant chondrodysplasia punctata (or Conradi-Hünermann-Happle syndrome; see this term) is characterized by the association of asymmetrical limbs, lamellar ichthyosiform erythroderma and cataract that may be unilateral. Intelligence is normal. The disease predominantly affects females and is severe or even lethal in males. Brachytelephalangic chondrodysplasia (see this term) associates severe facial dysmorphism (Binder's maxillonasal dysostosis; see this term), calcifications predominantly found in the tarsus and lower limbs, and hypoplastic distal phalanges. Stature and intelligence are normal to near-normal. Other forms of non-rhizomelic chondrodysplasia punctata include chondrodysplasia punctata tibial-metacarpal type, Toriello-Higgins-Miller syndrome and chondrodysplasia punctata, Sheffield type (see these terms).
Etiology
X-linked dominant chondrodysplasia punctata is transmitted in an X-linked dominant manner and is caused by mutations in the EBP gene encoding an enzyme involved in cholesterol metabolism. Brachytelephalangic chondrodysplasia is inherited in an X-linked recessive manner and is caused by a mutation in the ARSE gene.
Diagnostic methods
Chondrodysplasia punctata may be detected by ultrasound follow up, most often in the later stages of pregnancy, but identification of the exact form requires biochemical investigations (screening for abnormal sterols and long chain fatty acid analysis) of amniotic fluid samples.
Differential diagnosis
Maternal intake of anticoagulants during pregnancy, deficiency of vitamin K-dependent coagulation factors and maternal vitamin K deficiency (see these terms) can cause symptoms that are very similar to those of brachytelephalangic chondrodysplasia punctata. Calcifications around the epiphyses may also be caused by fetal alcohol syndrome (see this term) and may be seen in fetuses born to mothers with disseminated lupus erythematosus (see this term).
Management and treatment
Treatment should be adapted depending on the form of chondrodysplasia punctata present.
Prognosis
Prognosis is very variable.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Non-seminomatous germ cell tumor of testis

A form of testicular germ cell tumor occurring in the third decade of life with a usually painless unilateral mass in the scrotum or, in some cases, with gynaecomastia and/or back and flack pain. The clinical course is more aggressive than testicular seminomatous germ cell tumors with rapid involvement of blood vessels and a poorer prognosis. Histologically, the tumour can be either undifferentiated (embryonal carcinoma), differentiated (teratoma, yolk sac tumor, choriocarcinoma), or can consist of a mixture of seminomatous and nonseminomatous components.


Non-specific early-onset epileptic encephalopathy

A rare infantile epilepsy syndrome characterized by early onset of seizures of variable type and severity, potentially associated with a spectrum of clinical signs and symptoms including delay or lack of psychomotor development, intellectual disability, poor or absent speech development, behavioral abnormalities, hypotonia, movement disorders, spasticity, microcephaly, and dysmorphic facial features, among others. Brain imaging findings are also variable and may include cerebral atrophy or white matter abnormalities.


A rare idiopathic interstitial pneumonia characterized by temporally uniform alveolar and interstitial mononuclear cell inflammation (cellular type) and/or fibrosis of the alveolar walls (fibrotic type) with preserved alveolar architecture. Other types of interstitial lung disease must be excluded. Symptoms are non-specific and include dyspnea, cough, and often constitutional symptoms such as fever and fatigue. Pulmonary function test reveals a restrictive pattern. Computed tomography shows predominantly lower lobe subpleural reticular changes, traction bronchiectasis, and ground-glass opacities. The cellular type of the disease is less common but carries a better prognosis.


Non-specific syndromic intellectual disability

A rare genetic intellectual disability characterized by the association of intellectual disability with variable other anomalies in the absence of a well-characterized syndrome. Associated abnormalities may include facial dysmorphism, neurological signs and symptoms, behavioral problems, and abnormalities of various other organ systems.


Non-spherocytic hemolytic anemia due to hexokinase deficiency

Nonspherocytic haemolytic anaemia due to hexokinase deficiency is characterised by severe hemolysis, appearing in infancy. Seventeen affected families have been reported so far. Transmission is autosomal recessive. Mutations have been described in HK1, the gene that encodes red blood cell-specific hexokinase-R.


A wide spectrum of malformations involving the distal anus and rectum as well as the urinary and genital tracts, which can affect boys and girls.

Summary:
Epidemiology
They occur in approximately 1 in 5000 live births.
Clinical description
Defects range from mild anal anomalies to complex cloacal malformations. They can therefore be classified into the following groups: imperforated anus without fistula, ARM with rectourinary or rectogenital fistula and complex ARM (cloaca). Associated anomalies include genitourinary defects (in approximately 50% of patients) and spinal anomalies. A cloaca is associated with a urological problem (such as obstructive uropathy) in 90% of babies and with hydrocolpos in 50%. Sacral anomalies (hemisacrum and sacral hemivertebrae) have been described; hemivertebrae may also affect the lumbar and thoracic spine, leading to scoliosis. A tethered spinal cord (in 25% of patients) may result in motor and sensory disturbances of the lower extremities. Syringomyelia and myelomeningocele can occur.
Etiology
The etiology remains unclear and is likely multifactorial. Familial cases have been described.
Diagnostic methods
The radiological evaluation of a newborn with imperforate anus should include an abdominal and pelvic ultrasound to evaluate for genitourinary defects as they need to be dealt with in the newborn period to avoid serious complications. Spinal ultrasound in the first three months of life and magnetic resonance imaging thereafter are useful radiological modalities for detecting spinal anomalies.
Differential diagnosis
ARM can occur in association with multisystem syndromes, such as Townes-Brocks syndrome, Currarino syndrome, Pallister-Hall syndrome, and Down syndrome (see these terms).
Genetic counseling
The risk of ARM for a sibling of a patient with ARM can reach 1%.
Management and treatment
Patients can either undergo a primary repair procedure (anoplasty) or a protective colostomy and definitive repair at a later date, depending on the malformation. The surgical approach to repairing these defects changed dramatically in 1980 with the introduction of the posterior sagittal approach, which allowed surgeons to view the anatomy of these defects clearly, to repair them under direct vision, and to learn about the complex anatomic arrangement between the rectum and genitourinary tract.
Prognosis
Early diagnosis, management of associated anomalies and efficient meticulous surgical repair can ensure a good functional outcome in terms of bowel and urinary control, and sexual function. However, fecal and urinary incontinence can occur due mainly to associated problems such as a poorly developed sacrum, deficient nerve supply, and spinal cord anomalies. For these patients, an effective bowel management program, including enema and dietary restrictions improves the quality of life.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Dr Marc LEVITT  - Pr Alberto PENA


Isolated brachycephaly is a relatively frequent nonsyndromic craniosynostosis consisting of premature fusion of both coronal sutures leading to skull deformity with a broad flat forehead and palpable coronal ridges.

Summary:
Epidemiology
Incidence at birth is in the range of 1/20,000.
Clinical description
The skull deformity is characterized by a short anteroposterior diameter with a compensatory increase in bitemporal width. Supraorbital recession and exorbitism may also be present. Brachycephaly may be associated with facial anomalies (midface hypoplasia, slight hypertelorism and bulging temporal fossae). Increased intracranial pressure (ICP) is frequent and may lead to intellectual deficit if left untreated. In adults, elevated ICP is associated with bony defects in the absence of treatment.
Etiology
The extent to which nonsyndromic brachycephaly is genetically determined is still uncertain. Although the majority of cases are sporadic, familial forms (accounting for 14% of all cases) have been reported, with dominant inheritance in around 10% of cases. In addition, recurrent (paternally inherited) P250R mutations in fibroblast growth factor receptor 3 (FGFR3; 4p16.3) were identified in 74% of familial cases, as well as in 17% of sporadic cases. Among patients carrying the P250R mutation, females are more severely and more frequently affected than males (female to male ratio of 2:1) and mild hearing impairment is common. Minor radiologic anomalies including brachydactyly or fusion of metacarpal bones may occur in some FGFR3 mutation carriers. A mutation in the TWIST 1 gene (7p21) has been reported recently in a single case of isolated bicoronal synostosis, but a genetic origin has not been confirmed for most remaining cases. Several other determinants might be involved including mechanical constraints during pregnancy and after birth.
Diagnostic methods
Diagnosis is based on clinical examination, radiologic studies, and 3D CT scans and/or MRI of the skull. Since postoperative morphological and functional outcomes appear to be better in non-carriers of the FGFR3 mutation, molecular screening is recommended for all families with nonsyndromic forms of brachycephaly.
Differential diagnosis
Clinical distinction between syndromic and nonsyndromic forms brachycephaly is often difficult owing to phenotypic variability in patients carrying the P250R mutation. Although the cranial appearance of some patients might be reminiscent of the Saethre-Chotzen or Pfeiffer syndromes (see these terms), the absence of obvious hand and/or feet anomalies is a hallmark of nonsyndromic brachycephalic patients. Marked bulging of temporal fossae, seen mainly in female carriers of the FGFR3 mutation, might be instructive for differential diagnosis.
Management and treatment
Cranial vault reconstructive surgery is the main treatment to improve skull shape and increase intracranial volume. This usually results in reduced ICP. Early identification of hearing loss allows timely intervention when required.
Prognosis
The intellectual outcome of patients after cranial expansion surgery is usually good. However, patients carrying the FGFR3 mutation are five times more likely to require a second operation and show a poorer post surgical outcome than non-carriers.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Jacky BONAVENTURE  - Pr Dominique RENIER


Non-syndromic bilambdoid and sagittal craniosynostosis

A rare cranial malformation syndrome characterized by the premature closure of both lambdoid sutures and the posterior sagittal suture, resulting in abnormal skull contour (frontal bossing, anterior turricephaly with mild brachycephaly, biparietal narrowing, occipital concavity) and dysmorphic facial features (low-set ears, midfacial hypoplasia). Short stature, developmental delay, epilepsy, and oculomotor dyspraxia have also been reported. Associated anomalies include enlargement of the cerebral ventricles, agenesis of the corpus callosum, Arnold-Chiari malformation type I, venous anomalies of skull, and hydrocephalus.


Deafness is the most frequent form of sensorial deficit. In the vast majority of cases, the deafness is termed nonsyndromic or isolated and the hearing loss is the only clinical anomaly reported. In developed counties, 60-80% of cases of early-onset hearing loss are of genetic origin.

Summary:
Epidemiology
Between 1 in 1,000 and 1 in 700 children were born with profound or severe hearing loss.
Clinical description
The majority of cases presenting at birth concern perceptive deafness (with a neurosensory origin associated with the inner ear) rather than conductive deafness (anomalies in the amplification of sound waves between the middle ear - tympanum and auditory ossicles - and the outer ear). Autosomal dominant forms are characterised by very early onset and bilateral hearing loss with varying degrees of severity (ranging from mild to profound). No malformations of the inner ear can be detected by CT scan. Mutations in the PDS gene are responsible for 7% of cases of childhood deafness. In these cases, the deafness is marked by early-onset, usually bilateral (but sometimes asymmetric) hearing loss with autosomal recessive transmission. This form of deafness is always associated with malformations of the inner ear that can be detected by CT scan. In rare cases, thyroid gland disease may also be present. For the autosomal dominant forms of deafness, mutations in the COCH gene result in progressive postlingual deafness associated with severe attacks of vertigo and subjective tinnitus. This form of deafness should be distinguished from Meniere's disease (see this term). Autosomal dominant mutations in the  WFS1 gene cause either a form of hearing loss affecting mainly low frequency sounds or deafness associated with optic atrophy.
Etiology
To date, 86 causative genes for sensorineural deafness have been identified and localised and 37 of these genes have been cloned. Eleven of these genes have been implicated in both isolated and syndromic forms of deafness. Mutations in the gene encoding connexin 26 appear to be responsible for the majority of cases of childhood perceptive deafness.
Diagnostic methods
Hearing loss can be evaluated by audiogram and grouped as either mild (loss between 20 and 40 dB), moderate (loss between 41 and 70 dB), severe (loss between 71 and 90 dB), profound (loss between 91 and 120 dB) or as cophosis (loss beyond 120 dB).
Genetic counseling
In 85% of cases, the deafness is transmitted as an autosomal recessive trait (DFNB type). Autosomal dominant inheritance accounts for between 10 and 15% of cases (DFNA type), whereas only 1% of cases are inherited as an X-linked trait (DFN type).
Management and treatment
Management should be multidisciplinary (involving a paediatrician, general practitioner, ORL specialist, speech therapist and hearing aid specialist). Hearing aids (either implanted or external) generally provide the only management option for improving hearing loss, although surgical treatment may sometimes be proposed for some forms of conductive hearing loss.

                            Last update:
                            July 2007

                            - Expert reviewer(s):
                            Dr Sandrine MARLIN


Hemimelia is a limb malformation characterized by the absence or gross shortening of the lower portion of one or more of the limbs. The condition is designated according to which bone of the distal arm or leg is absent or defective and includes fibular, radial, tibial, or ulnar hemimelia (see these terms). Hemimelia ranges in severity.


Non-syndromic male infertility due to sperm motility disorder is a rare, genetic, non-syndromic male infertility disorder characterized by infertility due to sperm with defects in their cilia/flagella structure, leading to absent motility or reduced forward motility in fresh ejaculate. Reduced semen volume, oligospermia and an increased number of abnormally structured spermatozoa is often present.


Isolated trigonocephaly is a nonsyndromic form of craniosynostosis characterized by the premature fusion of the metopic suture.

Summary:
Epidemiology
Incidence is estimated at 1/15,000 births. Males are more frequently affected than females (sex ratio of 2:1) and the frequency of trigonocephalic twins is unexpectedly high.
Clinical description
The premature closure of the metopic suture results in deformation of the anterior portion of the calvarium and a triangular-shaped forehead. In mild forms, only prominent ridging of the metopic suture is visible; while in more severe forms marked narrowing of the frontal and temporal regions affects the supraorbital rims leading to hypotelorism. The psychomotor development of patients is usually normal and the majority of cases are mild.
Etiology
The underlying genetic cause of isolated trigonocephaly remains to be delineated. However, the concordance rate of isolated trigonocephaly in monozygotic twins is 43%, suggesting that both genetic and environmental factors are involved in the etiology of this disorder.
Diagnostic methods
Diagnosis is based on clinical and ultrasound examination, radiological evaluation by X-rays, and 3D CT scans and/or MRI of the skull. Since fusion of the metopic suture normally occurs during early childhood, CT scans for metopic synostosis should be performed before 6 months of age to avoid misdiagnosis. Premature fusion of the metopic suture may occur both in syndromic and in nonsyndromic forms of synostosis.
Differential diagnosis
The differential diagnosis should include trisomy 13 and other chromosomal disorders (distal monosomy 9p and 11q), as well as C syndrome (see these terms), and is based on the presence of multiple anomalies (including facial dysmorphism, organ anomalies and intellectual deficit) in the syndromic forms. Fetal exposure to valproic acid during pregnancy usually leads to trigonocephaly, which in this case is often associated with intellectual deficit and dysmorphic features, and therefore fetal valproate syndrome (see this term) should also be included in the differential diagnosis.
Genetic counseling
Most cases are sporadic but familial forms with apparently autosomal dominant transmission have been reported (representing 7-8% of all cases).
Management and treatment
Surgery is the only treatment for correction of the skull deformation. Primary orbitocranioplasty is performed according to different techniques including reshaping with metallic fixation or use of primary bone grafting and resorbable fixation to expand the frontal region. Anterolateral expansion of the supraorbital bar and stabilization of the construct via bone grafting and resorbable fixation give the best esthetic outcome with a low incidence of reoperation.
Prognosis
The clinical outcome for patients having undergone surgery is usually satisfactory with a low requirement for additional interventions, especially in the mild forms. Recurrence of a prominent metopic ridge may occur in some rare cases.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Jacky BONAVENTURE  - Pr Dominique RENIER


A rare group of neurodegenerative disorders with a prenatal onset characterized by hypoplasia and/or atrophy of the cerebellum and pons. Involvement of supratentorial structures is variable. Multiple forms have been described based on severity, age of onset and clinical presentation.

Summary:
Epidemiology
Prevalence of pontocerebellar hypoplasias (PCH) is unknown. Most subtypes appear to be very rare.
Clinical description
PCH is a clinically heterogeneous group of disorders, characterized by hypoplasia and/or atrophy of cerebellum and pons. Atrophy of supratentorial structures is variably present. There is great clinical variation both between and within the different forms. Delayed or absence of cognitive and voluntary motor development, intellectual deficit, spasticity, chorea/dyskinesia, swallowing difficulties and epilepsy are common clinical findings.
Etiology
The majority of PCH cases encompass mutations in tRNA splicing endonuclease. Mutations responsible for PCH2, PCH4, PCH5 include mutations in TSEN2 (PCH2), TSEN34 (PCH2; 19q13.42), TSEN15 (1q25.3), and TSEN54 (PCH2 4, 5; 17q25.1). PCH6 is due to mutations in mitochondrial arginyl-tRNA synthetase (RARS2; 6q15) gene. Approximately half the cases of PCH1 are due to mutations in the gene EXOSC3 (9p13.2). In addition, mutations in VRK1 (14q32.2), EXOSC8 (13q13.3) and EXOSC9 (4q27) are associated with PCH1. PCH3 is caused by mutations in the PCLO gene (7q21.11). Mutations in TOE1 (1p34.1) underlie PCH7, PCH8 is caused by a loss-of-function mutation in the CHMP1A gene (16q24.3). PCH9 is caused by mutation in the AMPD2 gene (1p13.3), and PCH10 by mutations in the CLP1 gene (11q12.1). The two most recently described genes associated with PCH are TBC1D23 (3q12.1-q12.2), associated with PCH11, and COASY (17q21.2), linked to PCH12.
Diagnostic methods
Diagnosis is made on clinical symptoms and neuroradiological findings (magnetic resonance imaging; MRI). It can be confirmed by molecular genetic analyses. MRI demonstrates a pontocerebellar hypoplasia, with often more severely affected cerebellar hemispheres than vermis, atrophy of ventral pons and to a lesser extent the cerebral cortex. Other neuroanatomical features include a severe progressive microcephaly and ventriculomegaly.
Differential diagnosis
Differential diagnosis includes progressive cerebello-cerebral atrophy (PCCA), infantile cerebral and cerebellar atrophy (ICCA), congenital disorders of glycosylation type 1A and D, phosphoserine aminotransferase deficiency, certain congenital mitochondrial disorders, progressive encephalopathy with edema hypsarrhythmia and optic atrophy (PEHO) syndrome, dystroglycanopathies like Walker-Warburg syndrome, MEB-disease, Fukuyama congenital muscular dystrophy, lissencephaly, X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum, congenital fibrosis of the extraocular muscles type 3 (CFEOM3) with extraocular involvement, acquired cerebellar hypoplasia in extreme premature births (<32 weeks) which may disrupt normal brain development, and mutations in the CASK¬ gene, that cause Microcephaly and Pontocerebellar Hypoplasia (MICPCH).
Antenatal diagnosis
If the disease causing mutation is known in carrier parents, routine methods for prenatal testing or preimplantation genetic diagnosis are available.
Genetic counseling
Transmission is autosomal recessive and genetic counseling for the affected family is recommended. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic, as there is no cure for PCH, and involves medication for treatment of dystonia, dyskinesia and seizures, percutaneous endoscopic gastrostomy tube feeding and sometimes respiratory support may be necessary. Cot death, sleep apnea, rhabdomyolysis and malignant hyperthermia may be life threatening complications for PCH2 patients.
Prognosis
Prognosis is poor. Many children live only into infancy or childhood, although some affected individuals have lived into adulthood.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK


A rare, non-syndromic, congenital, urogenital tract malformation affecting males and characterized by penoscrotal, scrotal or perineal displacement of the urethral meatus, and commonly associated with curvation of the penis. The scrotum might appear bifid in severe cases, and the boy can also have a micropenis.

Summary:
Epidemiology
Posterior hypospadias occurs in about 5% to 9% of hypospadias, for which the mean birth prevalence is estimated to be 1/500 in Europe.
Clinical description
The consequences of hypospadias, apart from the appearance, include spraying of the urinary stream, inability to urinate in standing position, and later in life curvature, unless corrected, leads to difficulties during intercourse. Fertility problems and decreased satisfaction with genital appearance are more common. Severe hypospadias and concomitant undescended testis, is regarded as a disorder of sex development (DSD) and should be referred to special multidisciplinary teams for molecular and hormonal evaluation.
Etiology
Posterior hypospadias arises early during urethra development in fetal weeks 8-16. The malformation is generally considered ''complex'' with both a genetic and environmental background. To date, the two genes MAMLD1 (Xq28) and AR (Xq12) have been associated with the isolated form of posterior hypospadias. However, there are an increasing number of genes involved in sex development that may lead to hypospadias, either as a part of syndrome or a result of gonadal dysgenesis.
Diagnostic methods
The diagnosis is set by an external inspection of the penis, usually just after birth. Hormonal, genetic and anatomic evaluations are required when the hypospadias is part of a DSD.
Differential diagnosis
Differential diagnoses include congenital adrenal hyperplasia in girls and, in patients with an XY karyotype, androgen insensitivity syndrome, steroid 5-alpha-reductase deficiency and 17-beta-hydroxysteroid dehydrogenase 3 deficiency. In addition, infants are screened for WT1 mutations to exclude Denys-Drash syndrome.
Antenatal diagnosis
Ultrasound diagnosis is sometimes possible since the tip of the penis can be smaller and quadrangular.
Genetic counseling
The familial recurrence risk is difficult to determine due to the complex genetic and environmental factors involved; however, genetic counseling is recommended. For hypospadias in general, the risk that a brother of an affected boy will also have hypospadias is 9-17%. The risk for the next boy in a family with an affected father and son is 25%. Where MAMLD1 is responsible, mutations may occur sporadically or through X-linked inheritance.
Management and treatment
Current guidelines consider optimal age for hypospadias repair between 9 and 18 months, depending on the severity and the need for multiple procedures. Surgery for posterior hypospadias remains challenging and no single technique is applicable to all patients. Patients frequently require extra tissue to restore the missing urethra after correction of the curvature, usually the inner prepuce or, in redo surgery, buccal mucosal is used. Affected males should be followed up into adulthood by a urologist or andrologist.
Prognosis
There is a greater dissatisfaction with the genital appearance in patients treated for posterior and complex hypospadias. Lower urinary tract symptoms are common postoperatively. Sexual problems like anejaculation are more common in posterior hypospadias; although fertility is diminished, sexual life is generally regarded as satisfactory.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Agneta NORDENSKJÖLD


Isolated scaphocephaly is a form of nonsyndromic craniosynostosis characterized by premature fusion of the sagittal suture.

Summary:
Epidemiology
It is a relatively common malformation accounting for around 50% of all cases of nonsyndromic craniosynostosis and with an incidence of 1/5,000 live births. Males are more frequently affected than females (male/female ratio of 3.5:1) and the frequency of affected twins is unexpectedly high.
Clinical description
The premature fusion of the sagittal suture results in compensatory anteroposterior elongation of the skull. The mean cranial length is significantly increased and the sagittal suture is larger than normal. Frontal bossing and occipital bulging may occur depending on the extent of the premature fusion. Elevated intracranial pressure is rare and intelligence is usually normal.
Etiology
The underlying cause of isolated scaphocephaly remains to be determined: a mutation in the TWIST1 gene (7p21) has been reported in a single case. However, the concordance rate in monozygotic twins was found to be 30%, suggesting some cases might be genetically determined, whereas environmental determinants are involved in others.
Diagnostic methods
Diagnosis is based on clinical examination and radiological evaluation by X-rays, 3D CT scans and/or MRI of the skull.
Differential diagnosis
Sagittal synostosis can be isolated or occur as part of a syndrome (such as familial scaphocephaly with radioulnar synostosis or sagittal craniosynostosis with Dandy-Walker malformation and hydrocephalus; see these terms). The syndromic and nonsyndromic forms can be clearly distinguished due to the absence in isolated scaphocephaly of additional clinical features.
Genetic counseling
The majority of cases are sporadic but familial cases with autosomal dominant inheritance have been described (6% of all cases).
Management and treatment
Management may involve cranial vault reconstructive surgery to correct skull shape.
Prognosis
The clinical outcome of patients having undergone surgery is usually good with normal intelligence and psychomotor development.

                            Last update:
                            December 2008

                            - Expert reviewer(s):
                            Dr Jacky BONAVENTURE  - Pr Dominique RENIER


A group of rare, congenital, non-syndromic distal limb malformation disorders characterized by webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. The morphological anomaly can be unilateral or bilateral, symmetrical or asymmetrical, depending on the specific type.


A rare multisystem genetic disorder characterized by cutaneous lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features.

Summary:
Epidemiology
Exact prevalence and incidence rates for Noonan syndrome with multiple lentigines (NSML) are not known. About 300 cases have been described to date. A slight male predominance has been reported.
Clinical description
Patients with NSML have a characteristic facial appearance including a broad forehead, hypertelorism, ptosis, down-slanting palpebral fissures, a high-arched palate, and low-set posteriorly rotated ears. Pectus deformity is common. Multiple lentigines, presenting as flat, black-brown macules, are located mainly on the face, neck, and upper trunk, sparing the mucosa, and constitute a hallmark feature of the syndrome. Lentigines appear at 4 to 5 years of age and increase in number until puberty. Café-au-lait spots may also be observed alone or along with lentigines. About one quarter of patients show growth delay with short stature in adulthood. Cardiac defects include ECG (electrocardiogram) anomalies, pulmonary valve stenosis, progressive conduction defects and hypertrophic cardiomyopathy, and are found in about 50% of patients. Some affected individuals have abnormal genitalia: unilateral or bilateral cryptorchidism and hypospadias in about one third of affected males; urinary tract defects and, less commonly, ovarian abnormalities. Sensorineural hearing loss is a less common feature (20%). Intellectual disability is generally mild and affects about 30% of cases. NSML can be associated with the development of neuroblastoma, acute myeloid leukemia, and acute lymphoblastic leukemia.
Etiology
NSML is mainly caused by mutations in the PTPN11 gene (12q24.1). Mutations are different from those known to cause Noonan syndrome, explaining the distinct clinical phenotype. Some cases are reported to involve mutations in RAF1 (3p25) , BRAF (7q34), or MAP2K1 (15q22.1-q22.33; one patient). There may be other currently unidentified causative genes.
Diagnostic methods
Clinical diagnosis may be difficult because of the absence of characteristic lentigines. Patients may have an initial diagnosis of Noonan syndrome. Molecular genetic testing may be useful to confirm diagnosis or to distinguish between overlapping syndromes.
Differential diagnosis
The clinical presentation overlaps significantly with Noonan syndrome and the main distinguishing manifestation is multiple lentigines. Other differential diagnoses include cardio-facio-cutaneous, Costello, and Turner syndromes.
Antenatal diagnosis
Prenatal diagnosis is possible if a causative gene mutation has been identified in an affected family member.
Genetic counseling
NSML follows an autosomal dominant pattern of inheritance. The proportion of de novo mutations is unknown. Genetic counseling should be provided to affected families informing them that there is a 50% risk of transmission from an affected individual to their offspring.
Management and treatment
Isolated lentigines may be treated with cryosurgery or laser treatment. Treatment of lentigines may also include tretinoin and hydroquinone creams. Treatment of cardiovascular manifestations follows standard methods and periodic cardiac monitoring is recommended. Cryptorchidism in affected males is also treated with conventional techniques. Hearing loss may require hearing aids, educational support, or cochlear implantation.
Prognosis
Life expectancy is normal in most affected patients, with the exception of patients with severe hypertrophic cardiomyopathy. The prognosis is mainly related to the severity of cardiac manifestations.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Maria Cristina DIGILIO | ITHACA*

                                * European Reference Network


Noonan syndrome-like disorder with juvenile myelomonocytic leukemia

A rare, genetic, polymalformative syndrome characterized by a Noonan-like phenotype associated with increased risk of developing juvenile myelomonocytic leukemia (JMML). The Noonan-like (NS) phenotype includes dysmorphic facial features (i.e. high forehead, hypertelorism, downslanting palpebral fissures, ptosis, low-set ears, prominent philtrum and short neck with or without pterygium colli), developmental delay, hypotonia and small head circumference. It can be associated with congenital heart defects or cardiomyopathy, ectodermal anomalies, and short stature. The NS phenotype is subtle or even inapparent in a large proportion of subjects, but may occasionally be severe. Leukemia can be the only clinical manifestation of the syndrome.


Noonan syndrome-like disorder with loose anagen hair

A Noonan-related syndrome, characterized by facial anomalies suggestive of Noonan syndrome, loose anagen hair, frequent congenital heart defects, distinctive skin features (darkly pigmented skin, keratosis pilaris, eczema or ichtyosis), and short stature that is often associated with a growth hormone deficiency. Psychomotor delay with attention deficit/hyperactivity disorder (ADHD) is frequently observed.

Summary:
Epidemiology
To date, more than 70 cases have been reported in the literature.
Clinical description
At birth and during childhood, the clinical features generally observed in Noonan syndrome appear more severe, but the phenotype generally improves with age. In particular, macrocephaly, high and prominent forehead, loose anagen hair and diffuse dark skin pigmentation are the features that may be observed early at birth or in infancy. The facial features, reminiscent of Noonan syndrome, include high broad forehead, hypertelorism, palpebral ptosis and downward slanting palpebral fissures, low-set, thick, posteriorly rotated ears, deep philtrum, micrognathia, and short neck. Hair is sparse, thin, easily plucked and slow growing despite being in the anagen phase. The roots lack inner and outer sheaths. Other ectodermal anomalies, include darkly pigmented and hairless skin, eczema and occasionally neonatal ichthyosis. The voice is hypernasal. Congenital heart abnormalities are common and predominated by mitral valve dysplasia and septal defects; hypertrophic cardiomyopathy (HCM) is observed in approximately 25% of cases. Short stature is often associated with proven growth hormone (GH) deficiency. Patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GH deficiency. Pubertal development is variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the final height. A mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD) is frequent. Sporadic neurological abnormalities such as ventriculomegaly, focal epilepsy, chronic complex tics, moyayamoya syndrome and neuroblastoma have been reported.
Etiology
SHOC2 gene encodes a protein that is a positive modulator of the RAS-MAPK signaling pathway. The p.Ser2Gly change in SHOC2 creates an N-myristoylation site, resulting in constitutive targeting of the mutated protein to the plasma membrane and enhanced signaling through the MAPK cascade. PPP1CB gene is a component of RAS/MAPK pathway and missense mutations in PPP1CB have also been identified in patients with this phenotype.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by molecular testing.
Differential diagnosis
The principal differential diagnosis includes Noonan syndrome and the other related disorders.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. It may also be suspected prenatally due to ultrasound abnormalities.
Genetic counseling
Transmission is autosomal dominant; however, most cases arise de novo and thus the risk of sibling recurrence is low.
Management and treatment
A multidisciplinary approach is mandatory. Regular evaluations by a pediatrician, endocrinologist, cardiologist, dermatologist, neurologist, psychologist should be recommended. GH therapy is a possible approach for short stature.
Prognosis
No longitudinal data are available for the estimation of life expectancy. The phenotype often improves with age. Quality of life depends on the degree of multiorgan and cognitive impairment and on the rehabilitation program adopted.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Laura MAZZANTI | ITHACA* - Dr Annamaria PERRI  - Dr Emanuela SCARANO  - Dr Federica TAMBURRINO

                                * European Reference Network


A rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood.

Summary:
Epidemiology
The birth prevalence of Noonan syndrome (NS) is estimated between 1:1000 to 1:2500.
Clinical description
NS typically presents in the neonatal period with feeding difficulties and failure to thrive. Characteristic facial features are often more obvious in infancy : high broad forehead, hypertelorism, palpebral ptosis and downward slanting palpebral fissures, low-set, thick, posteriorly rotated ears, deep philtrum, micrognathia, curly hair and a short neck with sometimes a pterygium colli. With age, the face becomes triangular, with marked skinfolds. The most common congenital heart defect is pulmonary valve stenosis (50-60%) with pulmonic valve dysplasia and various types of cardiac malformations (atrial septal defects, ventricular septal defects ect.). Hypertrophic cardiomyopathy of antenatal onset is common (20%) and may be stable or rapidly progressive. Dilation of coronary arteries and moya-moya disease may develop with aging. Growth delay affects 50%, uncommonly associated with growth hormone deficiency. Weight gain is difficult and many patients remain lean throughout life. Major orthopedic manifestations include sternal deformity, talipes equinovarus, and progressive scoliosis (onset at adolescence). Skin is often dry and sometimes hyperkeratotic on hands and feet. Hair is curly and may be thick or sparse. Peripheral lymphedema may be present and may be progressive and extensive in some. Ocular anomalies (strabismus, refractive errors), and dental crowding are common. Hearing loss is present in 10%. Delayed speech and learning difficulties affect 30-40%. Intellectual disability (often mild) is present in 10-20%. Dyspraxia (clumsiness), attention deficit disorder, agitation, mood disorders and emotional disturbances are not rare, as well as difficulties in identifying and expressing emotions, which can lead to more difficult social interactions. Motor development and puberty are delayed and short stature is present in 50%. Unilateral or bilateral cryptorchidism is present in two-thirds of boys, and hypofertility may affect males, but not females. Thyroid dysfunction may occur. Coagulation defects are frequent but rarely clinically significant. In childhood, there is an increased risk of tumors and leukemias (noteworthy juvenile myelomonocytic leukemia), with a cumulative cancer risk of about 4% by age 20. The risk of common adult cancer does not appear increased.
Etiology
NS is caused by mutations in PTPN11 (12q24.13) seen in 50% of cases, SOS1 (2p22.1) in 15%, RAF1 (3p25.2), RIT1 (1q22) and LZTR1(22q11.21), and less commonly in other genes associated with the RAS/MAPK signaling pathway. The clinical spectrum of NS may differ slightly between causative genes, and some forms have been described as ''Noonan like'' (NS-like disorder with juvenile myelomonocytic leukemia and NS-like disorder with loose anagen hair).
Diagnostic methods
The diagnosis relies on clinical manifestations but may be difficult because of the highly variable presentation. Molecular genetic testing of the causative genes helps diagnosis and genetic counseling. Mild cases may remain undiagnosed and only brought to clinical attention in adulthood after the birth of a more severely affected child.
Differential diagnosis
Differential diagnoses include Cardio-Facio-Cutaneous syndrome, Costello syndrome, Neurofibromatosis type 1, Noonan syndrome with multiple lentigines (all RASopathies), Baraitser-Winter, Aarskog and Escobar syndromes.
Antenatal diagnosis
Prenatal diagnosis is possible on chorionic villi or amniotic fluid. Prenatal signs of NS are nonspecific: increased nuchal translucency, cystic hygroma and/or ascites (that may lead to fetal demise), polyhydramnios, cardiomyopathy and congenital heart defect.
Genetic counseling
Inheritance of NS is autosomal dominant, except LZTR1 which can be either dominant or recessive. Genetic counseling should be offered to affected families.
Management and treatment
Treatment requires a multidisciplinary approach. Cardiovascular anomalies are treated with standard approaches. Treatment of growth retardation with growth hormone is still controversial. Developmental disabilities should be addressed early.
Prognosis
The prognosis is variable since the presentation ranges from mild/unrecognized manifestations in adulthood to severe disorder with life-threatening heart disease or malignancy in infancy. Severe cardiomyopathy may lead to early demise.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Alain VERLOES | ITHACA*

                                * European Reference Network


A rare developmental defect during embryogenesis characterized by abnormal retinal development with congenital blindness. Common associated manifestations include sensorineural hearing loss and developmental delay, intellectual disability and/or behavioral disorders.

Summary:
Epidemiology
To date, more than 400 cases have been described. Affected patients are almost always male.
Clinical description
The ocular findings in affected males are usually bilateral and symmetrical. The iris, anterior chamber and cornea may be normal at birth but greyish-yellow elevated masses (pseudogliomas) are often observed behind the lens along with retinal vascular dysgenesis and leukocoria. Partial or complete retinal detachment develops within the first few weeks or months of life. In infancy and childhood, patients may develop cataracts, nystagmus, anterior/posterior synechiae, band keratopathy and a shallow anterior chamber with increased intraocular pressure. Phthisis bulbi is found later on, along with opacified corneas and sunken orbits. Vision varies from light perception to congenital complete blindness. Most affected males develop progressive asymmetrical sensorineural hearing loss starting in childhood (median age of onset is 12 years). Hearing loss may be severe and bilateral by mid-adulthood. Developmental delay and intellectual disability are found in about 20-30% of patients. Some have cognitive and psychosocial behavioral disorders, including psychosis. Other associated manifestations are highly variable and may include growth failure, microphthalmia, varied chronic seizure disorders, peripheral vascular disease (peripheral ulcers) and erectile dysfunction. Very rare cases of carrier females with retinal findings, such as retinal detachment, abnormal retinal vasculature with associated vision loss or mild sensorineural hearing loss, have been reported.
Etiology
Norrie disease is caused by mutations in the NDP gene (Xp11.4-p11.3), encoding the norrin cystine knot growth factor NDP which is involved in the vascular development of the eye and ear. A large number of disease-causing mutations have been identified.
Diagnostic methods
Diagnosis is based on the characteristic clinical ocular findings and can be confirmed by molecular genetic testing of NDP. No biochemical or functional assays are available. A causative mutation in the NDP gene is recovered in around 85% of male probands. If negative, search for a rearrangement should be conducted.
Differential diagnosis
Differential diagnosis includes retinoblastoma in cases with unilateral pseudoglioma, and other disorders related to NDP mutations such as retinopathy of prematurity, persistent hyperplastic primary vitreous, and familial exudative vitreoretinopathy.
Antenatal diagnosis
Prenatal testing for at-risk pregnancies is possible if the disease-causing mutation has been identified in the family. In rare cases, particularly where there is a family history, ocular abnormalities have been detected on ultrasonography in the third trimester.
Genetic counseling
Norrie disease is inherited in an X-linked manner. Rare de novo mutations have been reported. Genetic counseling should be offered to affected families. Where a female carries the mutation, there will be a 50% risk that male offspring will inherit the disease, and a 50% risk that female offspring will be carriers. Where a male is affected, male offspring are unaffected whereas female offspring are obligate carriers
Management and treatment
Many patients have complete retinal detachment at birth making treatment for preservation of sight difficult. Those that do not have complete retinal detachment may benefit from surgery or laser therapy. Enucleation of the eye may be required in rare cases. Hearing aids should be provided to correct hearing loss and cochlear implantation can be considered. Supportive therapy should be provided for behavioral disorders.
Prognosis
Overall health is generally good in patients with ND. Life expectancy may however be reduced due to general risks associated with the disabling manifestations of the disease.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Patrick CALVAS


A non-progressive autosomal dominant macular disorder of congenital or infantile onset characterized by loss of central vision, the accumulation of drusen in the macula and atrophy of photoreceptor cells with a variable phenotype at macular examination.


NPHP3-related Meckel-like syndrome is a rare, genetic, syndromic renal malformation characterized by cystic renal dysplasia with or without prenatal oligohydramnios, central nervous system abnormalities (commonly Dandy-Walker malformation), congenital hepatic fibrosis, and absence of polydactyly.


NRXN1-related severe neurodevelopmental disorder-motor stereotypies-chronic constipation-sleep-wake cycle disturbance

A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, severe intellectual disability and absence of expressive language. Muscular hypotonia, seizures, autistic behavior and stereotypic movements are common.

Summary:
Epidemiology
To date, 11 affected individuals have been described in the literature worldwide. The exact prevalence is not known.
Clinical description
The main clinical characteristics are global developmental delay and severe intellectual disability. Speech is usually absent or very limited. Motor development is moderately to severely delayed, with walking after 2 years or even inability to walk in some individuals. Muscular hypotonia, severe deficits in social interaction, and motor stereotypies are very common. Moreover, abnormal sleep-wake cycle, abnormality in breathing and chronic constipation may occur. Electroencephalogram abnormalities and seizures were observed in several individuals with variable onset between the first months of life and adolescence. Brain imaging is normal in the majority of cases, but may also show moderate cortical atrophy, cysts or asymmetry of the ventricular system. Additional features such as failure to thrive, pulmonary stenosis, valve or septal defects, hearing impairment, microcephaly, gastroesophageal reflux, early onset puberty and scoliosis are present in single or few cases. Mild but non-specific facial dysmorphisms, such as a broad mouth, strabismus or protruding tongue with drooling, have occasionally been described.
Etiology
The disorder is caused by homozygous or compound heterozygous intragenic deletions or truncating variants in the NRXN1 gene (2p16.3). NRXN1 belongs to the evolutionarily conserved family of neurexins, presynaptic transmembrane proteins and has an important role in synaptic function.
Diagnostic methods
Diagnosis is usually made by untargeted approaches such as chromosomal microarray analysis and/or multigene panel or exome sequencing. Detection of a heterozygous, deleterious variant in NRNX1 in an individual with a fitting phenotype should prompt careful investigation of the second allele.
Differential diagnosis
Differential diagnosis includes other non-specific severe neurodevelopmental disorders with or without seizures.
Antenatal diagnosis
Prenatal diagnosis and preimplantation-diagnostic are possible where the pathogenic variant(s) has/have been identified in an affected family member and/or carrier status in the parents has been confirmed.
Genetic counseling
Inheritance is autosomal recessive; 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. Heterozygous deletions or variants in NRXN1 are associated with an increased risk for variable neuropsychiatric abnormalities.
Management and treatment
Ongoing developmental assessments are required to tailor educational services to individual needs, e.g. physical, occupational, speech therapies and behavioral management strategies. For patients with seizures, the appropriate seizure management is required.
Prognosis
There are patients living in their fourth decade. Usually severe cognitive impairment is present with dependence on others help for daily living.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Dr Katalin HETZELT | ITHACA* - Pr Christiane ZWEIER

                                * European Reference Network


The null syndrome is part of the Pelizaeus-Merzbacher disease (PMD; see this term) spectrum and is characterized by mild PMD features associated with demyelinating peripheral neuropathy.

Summary:
Epidemiology
Its prevalence is unknown. It predominantly affects males.
Clinical description
The disease manifests during childhood. Patients may have mild developmental delay, delayed sitting and walking beginning usually in the first 2 to 3 years of life, later associated with mild peripheral neuropathy, mild spastic quadriparesis, hyperreflexia, Babinski signs, ataxia, and/or mild intellectual deficit.  Patients do not have nystagmus. Although they usually are ambulatory during childhood and have good speech, patients with the null syndrome tend to decline more rapidly beginning in adolescence or early adulthood compared to patients with other PMD forms.
Etiology
The syndrome is due to null mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).
Genetic counseling
The disease has an X-linked inheritance pattern.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


A rare tumor characterized by a rapidly growing mass usually arising along the midline, defined by the presence of NUTM1 rearrangements. Histopathological examination shows a poorly differentiated carcinoma, often with evidence of squamous differentiation. Patients present with unspecific signs and symptoms due to mass effect, depending on the location. Extensive local invasion of adjacent structures, lymph node involvement, and distant metastatic disease are often present at the time of diagnosis. Prognosis is generally poor.


A rare acquired motor neuron disease characterized by an initial unilateral weakness in the intrinsic hand muscles that eventually spreads to the opposite limb (with an asymmetrical distribution) and that has a very slow progression of muscular atrophy over a 20 year period.


A rare, genetic form of obesity characterized by morbid obesity, hypertension, type 2 diabetes mellitus and dyslipidemia leading to early coronary disease, myocardial infarction and congestive heart failure. Intellectual disability and decreased sperm counts or azoospermia have also been reported.


Obesity due to congenital leptin deficiency

Congenital leptin deficiency is a form of monogenic obesity characterised by severe early-onset obesity and marked hyperphagia.

Summary:
Epidemiology
It has been described in less than 30 patients.
Clinical description
Patients with congenital leptin deficiency are severely hyperphagic from early infancy and, although birthweight is normal, they rapidly become obese during early childhood. An increased susceptibility to infections has also been reported in these infants and appears to be associated with reduced numbers of circulating CD4+ T cells, and impaired T cell proliferation and cytokine release. Other features of the disorder include hyperinsulinaemia, advanced bone age, hypothalamic hypothyroidism and hypogonadotropic hypogonadism leading to a failure to undergo puberty.
Etiology
Leptin is an adipocyte-derived hormone that plays an important role in energy balance and appetite suppression. Whilst the majority of obese patients display hyperleptinaemia, patients with congenital leptin deficiency have undetectable levels of leptin in the serum. This absence of serum leptin is caused by homozygous frameshift or missense mutations in the ob gene (7q31.3) and is inherited as an autosomal recessive trait. However, a similar phenotype has been observed in three individuals from one consanguineous family who carried homozygous mutations in the gene encoding the leptin receptor (LEPR, 1p31).
Diagnostic methods
Family history, severe hyperphagia and early-onset obesity may lead to suspicion of a monogenic obesity syndrome. The diagnosis of congenital leptin deficiency can be confirmed by analysis of serum leptin levels or identification of mutations in the ob gene.
Management and treatment
Congenital leptin deficiency can be successfully treated with daily subcutaneous injections of recombinant human leptin, resulting in sustained positive effects on weight loss, reducing appetite, appropriate pubertal development and hyperinsulinaemia.
Prognosis
As a result, the prognosis for patients undergoing treatment appears to be excellent. However, misdiagnosed patients are at risk of developing the complications normally associated with severe obesity (in particular type 2 diabetes), with the prognosis being hampered further by an increased rate of mortality due to childhood infection.

                            Last update:
                            May 2007

                            - Expert reviewer(s):
                            Pr Sebastiano FILETTI


Obesity due to leptin receptor gene deficiency

A rare, genetic, non-syndromic, obesity disease characterized by severe, early-onset obesity, associated with major hyperphagia and endocrine abnormalities, resulting from leptin receptor deficiency.


Obesity due to melanocortin 4 receptor deficiency

Melanocortin 4 receptor (MC4R) deficiency is the commonest form of monogenic obesity identified so far. MC4R deficiency is characterised by severe obesity, an increase in lean body mass and bone mineral density, increased linear growth in early childhood, hyperphagia beginning in the first year of life and severe hyperinsulinaemia, in the presence of preserved reproductive function.

Summary:
Epidemiology
The prevalence in the general population is probably around 1 in 2000. The prevalence of MC4R mutations has been estimated at between 0.5 and 1% in obese adults (body mass index >30) with higher values among populations with severe childhood-onset obesity and variability between ethnic groups.
Etiology
MC4R is a G protein-coupled receptor involved in the hypothalamic leptin-melanocortin signalling pathway. Activation of the MC4R plays a key role in the maintenance of energy homeostasis and is associated with suppression of food intake. The majority of patients described so far are carriers of heterozygous mutations in the MC4R gene (18q22). Rare homozygous carriers have been described and display a more severe phenotype. However, one homozygous patient with complete absence of MC4R function has been reported and did not display hyperinsulinaemia.
Diagnostic methods
The majority of MC4R deficient cases reported so far have been identified through genetic screening of large cohorts of obese patients, however, diagnosis may be suspected on the basis of the clinical features of the disorder and confirmed by detection of a MC4R mutation.
Genetic counseling
MC4R deficiency is transmitted in a codominant manner, with expressivity and penetrance varying between ethnic groups.
Management and treatment
At present, there is no specific treatment for MC4R deficiency. However, future development of small molecule MC4R agonists might lead to the generation of highly effective treatments for this disorder.
Prognosis
As with other forms of obesity, the prognosis is dependent on the complications present, with obese patients being at increased risk of cardiovascular disease, cancer and type 2 diabetes.

                            Last update:
                            May 2007

                            - Expert reviewer(s):
                            Pr Sebastiano FILETTI


Obesity due to pro-opiomelanocortin deficiency

Pro-opiomelanocortin (POMC) deficiency is a form of monogenic obesity resulting in severe early-onset obesity, adrenal insufficiency, red hair and pale skin.

Summary:
Epidemiology
It is has been described in less than 10 patients.
Clinical description
Patients with POMC deficiency usually present in the neonatal period with hypoglycaemic seizures, hyperbilirubinaemia and cholestasis to due to secondary congenital hypocortisolism. Hyperphagia is noted from the first weeks of life leading to severe obesity before one year of age. Subclinical hypothyroidism was also reported.
Etiology
Complete POMC deficiency is caused by homozygous or compound heterozygous loss-of-function mutations in the POMC gene (chromosome 2p23.3). POMC is regulated by leptin and is cleaved by prohormone convertases to produce the melanocortin receptor (MC-R) ligands adrenocorticotrophin (ACTH) and melanocyte-stimulating hormones (MSH) alpha, beta and gamma. The red hair pigmentation, adrenal insufficiency and obesity are caused by deficiencies in the ligands and subsequent lack of activation of the MC1, MC2, and MC4 receptors, respectively. In addition to complete POMC deficiency, a few individuals with isolated deficiency of the MC4-R POMC-derived ligand, beta-MSH, have also been described. These individuals carry a distinct POMC mutation in the region encoding beta-MSH. This isolated deficiency of beta-MSH leads to a clinical phenotype similar to that observed in MC4-R deficiency (childhood obesity, hyperphagia and increased linear growth) but is not associated with red hair or adrenal insufficiency.
Diagnostic methods
Diagnosis of complete POMC deficiency may be suspected on the basis of the clinical manifestations of the disease and can be confirmed by identification of mutations in the POMC gene. Analysis of the serum reveals an absence of pituitary-derived POMC peptides, even after stimulation.
Differential diagnosis
Differential diagnosis includes combined pituitary hormone deficiencies, which can be excludedby multiple pituitary hormone stimulation tests.
Genetic counseling
Complete POMC deficiency is transmitted as an autosomal recessive trait.
Management and treatment
At present, there is no specific treatment. The neonatal complications of POMC deficiency may lead to lethal hepatic failure if left untreated, with patients requiring prompt and long-term hydrocortisone substitution therapy. Advances in melanocortin peptide therapy may lead to the development of MC4R agonists capable of improving melanocortin function in these patients. However, an initial 3-month trail with intranasal administration the ACTH 4-10 melancortin fragment did not lead to a reduction in body weight. Administration of thyroid hormone was also found to have no effect on the obesity.
Prognosis
Although the specific prognosis for this disease has not yet been defined, it is likely these patients are at increased risk of complications (cardiovascular disease, cancer and type 2 diabetes) present in other obese patients.

                            Last update:
                            May 2007

                            - Expert reviewer(s):
                            Pr Sebastiano FILETTI


Obesity due to prohormone convertase I deficiency

A rare genetic endocrine disease characterized by early onset of severe intractable diarrhea and intestinal malabsorption, followed by obesity and hormonal deficiencies due to insufficient activation of several prohormones, resulting in hypocortisolism, hypothyroidism, diabetes insipidus, hypogonadism, growth deficiency, and diabetes mellitus. Extent and age of onset of hormone deficiencies are variable between patients.


A rare, genetic form of obesity characterized by severe early-onset obesity, hyperphagia, and variable presence of cognitive impairment and behavioral disorder, including autistic spectrum behavior, impaired concentration and memory deficit. Some patients present with Prader-Willi-like features such as hypotonia, developmental delay, intellectual disability, short stature, hypopituitarism and dysmorphic facial features.


Obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome is characterised by precocious obesity, congenital hypothyroidism, neonatal colitis, cardiac hypertrophy, craniosynostosis and developmental delay. It has been described in two brothers, one of whom died within the first month of life. The parents of the two children were nonconsanguineous and in good health, however, the pregnancies were complicated by a maternal HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelets). The mode of inheritance has not yet been clearly established.


A rare congenital disorder of copper metabolism that is principally characterized by bony exostoses (including the pathognomonic occipital horns), and connective tissue manifestations with cutis laxa and bladder diverticula. Central nervous system involvement is variable.

Summary:
Epidemiology
Occipital horn syndrome (OHS) is a very rare X-linked disease and the exact prevalence is unknown. To date approximately 35 cases have been reported and all but one were male.
Clinical description
Age of onset ranges from infancy to childhood. Observations at birth may include cephalhematoma (12% of cases), loose and wrinkled skin, and umbilical or inguinal hernias. About one third of all patients primarily present with central nervous system involvement (hypotonia, developmental delay and/or seizures). Initial clinical presentation may occur later with bladder diverticula or skeletal manifestations. Bladder diverticula affects the majority of patients (>80%) and may manifest through recurrent urinary tract infections or pollakisuria. The most typical skeletal manifestation (present in 96% of all patients) is an exostosis on the occiput at the insertion of the trapezoid muscle (occipital horn), but exostoses may also occur on the tibia and radius. Other, more variable, skeletal features are hammer-shaped claviculae, scoliosis, pectus deformity, coxa valga, genua valga as well as dislocations of the radial head. Less frequently reported skeletal manifestations include bowing of the long bones, mid-diaphyseal broadening, metaphyseal spurring, rounding of the iliac wings and, rarely, osteopenia. Facial features become distinctive with age and includes a long face (46%), large ears (38%), sagging cheeks (45%) and coarse hair (74%). Trichoscopy may show pili torti. The skin is often hyperextensible and soft with fine wrinkling on the hands and feet. Skin redundancy is remarkable on the belly. Vascular tortuosity is common in the intracranial arteries (65%), but may also affect the cervical, splenic and splanchnic circulation and imposes a risk for aneurysm formation. Aortic root dilatation and dissection may rarely occur. Dysautonomia with postural orthostatic hypotension, temperature instability and chronic diarrhea is present in most patients (>90%). About half of all patients show a delayed motor development due to muscle hypotonia and joint hypermobility, and may report unusual clumsiness. Distal motor neuropathy has been recorded in at least one patient. About half of all patients have intellectual disability (ID) which is usually mild, but moderate to severe impairment may occur.
Etiology
OHS is due to pathogenic variants (missense, frameshift and splice variants) in the ATP7A gene (Xq21.1) encoding the copper-transport ATPase 1. OHS is allelic with Menkes disease; there are no clear genotype-phenotype correlations, nor a correlation between the type or location of the variant and serum copper levels. However, certain variants may lead to a partially functional protein or reduced amounts of an otherwise normal protein.
Diagnostic methods
Diagnosis is based on clinical features. Radiography shows the characteristic occipital horns. Diagnosis is confirmed by identification of a pathogenic variant.
Differential diagnosis
Menkes disease is the main differential diagnosis and allelic to OHS. Other conditions to be considered include other forms of cutis laxa, including autosomal dominant cutis laxa, and autosomal recessive cutis laxa type 1a and 1c, Ehlers-Danlos syndrome, dermatosparaxis type, and hereditary multiple exostoses.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is X-linked recessive. Genetic counseling should be offered to couples where the mother is a carrier of a pathogenic variant, informing them that the risk for a male fetus to be affected is 50% at each pregnancy. The possibility of germ-line mosaicism should be discussed when counselling non-carrier mothers of singleton cases; although not yet described for OHS it has been described for Menkes disease.
Management and treatment
Treatment is symptomatic. No data exist on early parenteral copper-histidine supplementation. Notably, individuals with OHS are at increased risk for post-surgery apnea, and should benefit from prolonged post-surgery monitoring.
Prognosis
Prognosis is variable in OHS. Most patients reach adulthood. Risks for early demise include seizures, bladder rupture, vascular ruptures and postsurgical apnea. Inguinal hernia often recur after surgery.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Bert CALLEWAERT | ERN-Skin* - Pr Zeynep TÜMER | ITHACA*

                                * European Reference Network


A rare, genetic, cerebral malformation characterized by the presence of cortical smoothening with loss of secondary and tertiary gyri, associated with an excessive number of small, irregular gyri with increased cortical thickness, located in the occipital lobes. Patients usually present with seizures (including myoclonic-astatic, absence, atypical absence, vision loss, myoclonic-atonic, generalized tonic-clonic) and variable (absent to moderate) developmental and/or intellectual delay.


Occult macular dystrophy is a rare, genetic retinal dystrophy disease characterized by bilateral progressive decline of visual acuity, due to retinal dysfunction confined only to the macula, associated with normal fundus and fluorescein angiograms and severly attenuated focal macular and multifocal electroretinograms.


Occupational allergic alveolitis designates a hypersensitivity pneumonitis (see this term) resulting from the inhalation of an antigen to which an individual has been previously sensitized in his/her occupational environment. Symptoms vary depending on the antigen and the form (acute, subacute, chronic) of the disease. They may be cough, dyspnea, chills, fever, weight loss, loss of appetite and general malaise