Thanatophoric dysplasia type 1 (TD1) is a form of TD (see this term) characterized by short, bowed femurs, micromelia, narrow thorax, and brachydactyly. Epidemiology The prevalence is unknown but it is more common than TD 2 (see this term). Clinical description TD1 presents in the prenatal period (in the first to second trimester) with growth deficiency of the limbs of less than 5%, bowed femurs (like a telephone receiver), shortened ribs, and platyspondyly of the vertebrae. Distinctive facial features include macrocephaly, large anterior fontanel, frontal bossing, proptosis and low nasal bridge. Neonates usually die shortly after birth due to respiratory insufficiency and/or spinal cord/brain stem compression.

Summary Clinical characteristics. Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified. Diagnosis/testing. The diagnosis of Legius syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in SPRED1 identified by molecular genetic testing. Management. Treatment of manifestations: Consideration of behavioral modification and/or pharmacologic therapy for those with ADHD; physical, speech, and occupational therapy for those with identified developmental delays; and individualized education plans for those with learning disorders.

A number sign (#) is used with this entry because of evidence that Legius syndrome (LGSS) is caused by heterozygous mutation in the SPRED1 gene (609291) on chromosome 15q14. Description Legius syndrome is an autosomal dominant disorder that shows some similarities to neurofibromatosis type I (NF1; 162200), which is caused by mutation in the neurofibromin gene (613113); however, Legius syndrome is less severe. Individuals with Legius syndrome typically have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. Legius syndrome is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin, and thus may be considered a RASopathy (review by Brems et al., 2012).

Legius syndrome, also known as NF1-like syndrome, is a rare, genetic skin pigmentation disorder characterized by multiple café-au-lait macules with or without axillary or inguinal freckling. Epidemiology The prevalence of Legius syndrome is not known. Fewer than 200 cases have been reported to date. Prevalence may be higher than expected due to misdiagnosis of cases as neurofibromatosis type 1 (NF1, see this term). The incidence of NF1 is reported to be 1/3000, and about 2% of patients fulfilling diagnostic criteria for NF1 are found to have the genetic mutation underlying Legius syndrome ( SPRED1 ). Clinical description The clinical presentation of Legius syndrome is very similar to that of NF1.

Legius syndrome Other names Neurofibromatosis 1-like syndrome [1] This condition is inherited in an autosomal dominant manner. Symptoms café au lait spots ; +/- learning disabilities [2] Usual onset at birth Causes Mutations in the SPRED1 gene [3] Diagnostic method Clinical findings, Genetic test [4] Differential diagnosis neurofibromatosis type I (NF-1) Treatment Physical therapy, Speech therapy [2] [1] Prognosis good Frequency rare (estimated at 1:46,000-1:75,000) [2] Legius syndrome ( LS ) is an autosomal dominant condition characterized by cafe au lait spots . [3] It was first described in 2007 and is often mistaken for neurofibromatosis type I (NF-1). It is caused by mutations in the SPRED1 gene. [5] [6] It is also known as neurofibromatosis type 1-like syndrome ( NFLS ). [1] Contents 1 Symptoms and signs 2 Cause 3 Mechanism 4 Diagnosis 4.1 Differential diagnosis 5 Treatment 6 See also 7 References 8 Further reading 9 External links Symptoms and signs [ edit ] See also: List of conditions associated with café au lait macules larger café au lait spot on right underarm Nearly all individuals with Legius syndrome show multiple café au lait spots on their skin. [7] Symptoms may include: [2] Freckles in the axillary and inguinal skin fold Lipomas , developing in adulthood Macrocephaly Learning disabilities ADHD Developmental delay Features common in neurofibromatosis – like Lisch nodules (iris hamartomas diagnosed on slit lamp exam), bone abnormalities, neurofibromas , optic pathway gliomas and malignant peripheral nerve sheath tumors – are absent in Legius syndrome. [1] Cause [ edit ] CHR 15 Legius syndrome is a phakomatosis [8] and a RASopathy , a developmental syndrome due to germline mutations in genes. [7] [9] The condition is autosomal dominant in regards to inheritance and caused by mutations to the SPRED1 gene at chromosome 15 , specifically 15q14 (or (GRCh38): 15:38,252,086-38,357,248). [10] [11] The gene in question demonstrates almost 100 mutations. [1] Mechanism [ edit ] A mutated SPRED1 protein adversely regulates Ras-MAPK signaling , which is a chain of proteins in a cell that sends signals from the surface of a cell to the nucleus which in turn causes the symptoms of this condition. [2] [12] Diagnosis [ edit ] Genetic testing is necessary to identify the syndrome. The DNA test is necessary sometimes, because symptoms may not be sufficient to definitely diagnose this condition. [4] [1] [13] Differential diagnosis [ edit ] The symptoms of Legius syndrome and NF-1 are very similar; An important difference between Legius syndrome and NF-1 is the absence of tumor growths Lisch nodules and neurofibromas which are common in NF-1. [2] A genetic test is often the only way to make sure a person has LS and not NF-1; the similarity of symptoms stem from the fact that the different genes affected in the two syndromes code for proteins that carry out a similar task in the same reaction pathway. [ medical citation needed ] Treatment [ edit ] Management of Legius syndrome is done via the following: [2] [1] Physical therapy Speech therapy Pharmacologic therapy (e.g. methylphenidate for ADHD) [14] The prognosis of this condition is generally considered good with appropriate treatment. [ citation needed ] See also [ edit ] List of cutaneous conditions List of genes mutated in cutaneous conditions References [ edit ] ^ a b c d e f g RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Legius syndrome" . www.orpha.net . Retrieved 2017-06-01 . ^ a b c d e f g Stevenson, David; Viskochil, David; Mao, Rong (1993).

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome 15q15.3. Two of the genes residing in this region are STRC (606440) and CATSPER2 (607249). STRC alterations cause autosomal recessive nonsyndromic sensorineural deafness-16 (DFNB16; 603720). Description Deafness-infertility syndrome (DIS), characterized by early-onset deafness in both males and females and exclusive male infertility, is caused by homozygous deletion of the STRC and CATSPER2 genes on chromosome 15q15.5 (summary by Vona et al., 2015). Clinical Features Dgany et al. (2002) reported a nonconsanguineous French family in which a 56-year-old male and his 2 brothers suffered from type I congenital dyserythropoietic anemia (CDA1; 224120), infertility, and nonsyndromic deafness.

Deafness-infertility syndrome (DIS) is a very rare syndrome associating sensorineural deafness and male infertility. Epidemiology It has been reported in fewer than 5 families. Etiology Male infertility is caused by abnormal spermatozoid morphology and motility. DIS is due to a contiguous gene deletion at chromosome 15q15.3 including 2 genes CATSPER2 and STRC , and is inherited in an autosomal recessive manner: affected males are homozygous for the deletion, parents are asymptomatic carriers and homozygous females are deaf but not infertile.

Globozoospermia is a rare form of male infertility . Men affected by this condition have abnormal sperm with a round (rather than oval) head and no acrosome (a cap-like covering which contains enzymes that break down the outer membrane of an egg cell). As a result of these abnormalities, the sperm are unable to fertilize an egg cell, leading to male factor infertility. Approximately 70% of men with globozoospermia have changes (mutations) in the DPY19L2 gene, which are inherited in an autosomal recessive manner. In the remaining cases, the underlying cause of the condition is unknown; however, researchers suspect that mutations in other genes likely cause globozoospermia. Although there is currently no cure for the condition, certain assisted reproductive technologies ( ICSI combined with assisted egg cell activation, specifically) can help men affected by the condition conceive children.

A number sign (#) is used with this entry because spermatogenic failure-9 (SPGF9) is caused by homozygous or compound heterozygous mutation in the DPY19L2 gene (613893) on chromosome 12q14. Description Spermatogenic failure-9 is associated with globozoospermia, a rare phenotype of primary male infertility characterized by the production of a majority of round-headed spermatozoa without an acrosome (summary by Harbuz et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). Clinical Features Kilani et al. (2004) studied a consanguineous Jordanian family in which 5 infertile brothers had a complete form of globozoospermia, with 100% of spermatozoa having round heads. There were 5 additional sibs in the family, including 2 sisters and 3 brothers, who were naturally fertile and had 3 to 7 children each.

A number sign (#) is used with this entry because Alexander disease (ALXDRD) is caused by heterozygous mutation in the gene encoding glial fibrillary acidic protein (GFAP; 137780) on chromosome 17q21. Description In decreasing order of frequency, 3 forms of Alexander disease are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset.

The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.

The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.

Rare genetic disorder of the white matter of the brain Alexander disease Brain of a 4-year-old boy with Alexander disease showing macroencephaly and periventricular leukomalacia (note brownish discoloration around the cerebral ventricles ) Specialty Endocrinology , neurology Alexander disease is a very rare autosomal dominant leukodystrophy , which are neurological conditions caused by anomalies in the myelin which protects nerve fibers in the brain. The most common type is the infantile form that usually begins during the first 2 years of life. Symptoms include mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal increase in head size and seizures. The juvenile form of Alexander disease has an onset between the ages of 2 and 13 years. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control.

Alexander disease is a type of leukodystrophy characterized by the destruction of the myelin sheath (the fatty covering that acts as an insulator around nerve fiber) and abnormal protein deposits known as Rosenthal fibers. Most cases of Alexander disease begin before age 2 years (the infantile form). Symptoms of the infantile form include an enlarged brain and head, seizures, stiffness in the arms and/or legs, intellectual disability, and delayed physical development. Less frequently, onset occurs later in childhood (the juvenile form) or adulthood. Common problems in juvenile and adult forms of Alexander disease include speech abnormalities, swallowing difficulties, and poor coordination.

Summary Clinical characteristics. Alexander disease, a progressive disorder of cerebral white matter caused by a heterozygous GFAP pathogenic variant, comprises a continuous clinical spectrum most recognizable in infants and children and a range of nonspecific neurologic manifestations in adults. This chapter discusses the spectrum of Alexander disease as four forms: neonatal, infantile, juvenile, and adult. The neonatal form begins in the first 30 days after birth with neurologic findings (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive), followed by severe developmental delay and regression, seizures, megalencephaly, and typically death within two years. The infantile form is characterized by variable developmental issues: initially some have delayed or plateauing of acquisition of new skills, followed in some by a loss of gross and fine motor skills and language during in the first decade or in others a slow disease course that spans decades. Seizures, often triggered by illness, may be less frequent/severe than in the neonatal form.

As a result, the abnormal glial fibrillary acidic protein likely accumulates in astroglial cells, leading to the formation of Rosenthal fibers, which impair cell function. It is not well understood how impaired astroglial cells contribute to the abnormal formation or maintenance of myelin, leading to the signs and symptoms of Alexander disease.

Reynolds syndrome (RS) is an autoimmune disorder characterized by the association of primary biliary cirrhosis (PBC) with limited cutaneous systemic sclerosis (lcSSc) (see these terms). Epidemiology The prevalence of systemic sclerosis (SSc) in PBC patients is 5-15%. Conversely, the prevalence of PBC in SSc patients is about 2%. Females are more affected. Clinical description Onset occurs between 30-65 years. RS associates the features of PBC (fatigue, pruritus due to cholestasis, hepatomegaly) with most features of lcSSC (cutaneous calcifications, digital ulcers, facial telangiectasias, calcinosis, Raynaud's phenomenon, esophageal involvement and sclerodactyly). In 50% of cases, symptoms of scleroderma occur prior to those of PBC.

Reynolds syndrome is an autoimmune disease characterized by the co-occurrence of primary biliary cholangitis (PBC) and limited cutaneous systemic sclerosis (LCSS). The signs and symptoms of Reynolds syndrome therefore include those of both PBC and LCSS. People with PBC may have symptoms such as tiredness (fatigue) and itchy skin (pruritus), as well as an enlarged liver (hepatomegaly). Signs and symptoms of LCSS may include calcium deposits in the skin, tissues, and organs (calcinosis); sores on the fingers and toes ( digital ulcers ); facial telangiectasias ; Raynaud's phenomenon ; esophageal dysfunction (such as acid reflux); and sclerodactyly (tightening of the skin on the fingers and toes). Reynolds syndrome typically occurs sporadically, affecting only one person in a family.

A number sign (#) is used with this entry because of evidence that Reynolds syndrome is caused by heterozygous mutation in the LBR gene (600024) on chromosome 1q42. One such patient has been reported. Clinical Features Reynolds et al. (1971) reported 6 unrelated women, ranging in age from 38 to 51 years, with a constellation of clinical features, including liver disease, telangiectasia, Raynaud phenomenon, and variable features of scleroderma (181750). The liver disease was characterized by pruritus, jaundice, hepatomegaly, increased serum alkaline phosphatase, and positive serum mitochondrial autoantibodies, all consistent with primary biliary cirrhosis (PBC; 109720). Liver biopsies showed variable subtle features of PBC, including absence of cholangioles and inflammatory cells, in most patients. Telangiectases were present on the fingerpads of all patients, on the lips in 5, and in the gastrointestinal tract in at least 2.

Lemierre syndrome is a rare, potentially lethal, oropharyngeal infectious disease occurring in immunocompetent adolescents and young adults that is mainly due to Fusobacterium necrophorum and that is characterized by septic thrombophlebitis of the internal jugular vein that leads to septic, usually pulmonary, embolism, associated with ENT (ear, nose, and throat) infection that manifests with fever, neck pain, and tonsillopharyngitis.