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FG syndrome 4(FGS4)

MedGen UID:: 336965
•Concept ID:: C1845546
•: Disease or Syndrome

Synonyms:	FGS4; X-Linked Intellectual Disability with or without Nystagmus

Gene (location): Gene(s) directly associated with this condition or phenotype.	CASK (Xp11.4)

Monarch Initiative:	MONDO:0010318
OMIM®:	300422

Disease characteristics

Excerpted from the GeneReview: CASK Disorders

CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features. [from GeneReviews]

Authors:
Ute Moog | Kerstin Kutsche view full author information

Additional descriptions

From OMIM
FG syndrome-4 (FGS4) is an X-linked recessive intellectual developmental disorder characterized by congenital hypotonia, constipation, behavioral disturbances, and dysmorphic features (summary by Piluso et al., 2003). For a general phenotypic description and a discussion of genetic heterogeneity of FG syndrome, see FGS1 (305450). http://www.omim.org/entry/300422

From MedlinePlus Genetics
Additional features seen in some people with FG syndrome include widely set eyes (hypertelorism), an upswept frontal hairline, and a large head compared to body size (relative macrocephaly). Other health problems have also been reported, including heart defects, seizures, undescended testes (cryptorchidism) in males, and a soft out-pouching in the lower abdomen (an inguinal hernia).

FG syndrome is a genetic condition that affects many parts of the body and occurs almost exclusively in males. "FG" represents the surname initials of the first family diagnosed with the disorder.

FG syndrome affects intelligence and behavior. Almost everyone with the condition has intellectual disability, which ranges from mild to severe. Affected individuals tend to be friendly, inquisitive, and hyperactive, with a short attention span. Compared to people with other forms of intellectual disability, their socialization and daily living skills are strong, while verbal communication and language skills tend to be weaker.

The physical features of FG syndrome include weak muscle tone (hypotonia), broad thumbs, and wide first (big) toes. Abnormalities of the tissue connecting the left and right halves of the brain (the corpus callosum) are also common. Most affected individuals have constipation, and many have abnormalities of the anus such as an obstruction of the anal opening (imperforate anus). People with FG syndrome also tend to have a distinctive facial appearance including small, underdeveloped ears; a tall, prominent forehead; and outside corners of the eyes that point downward (down-slanting palpebral fissures). https://medlineplus.gov/genetics/condition/fg-syndrome

Clinical features

From HPO

Feeding difficulties in infancy

MedGen UID:: 436211
•Concept ID:: C2674608
•: Finding

Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.

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Sensorineural hearing loss disorder

MedGen UID:: 9164
•Concept ID:: C0018784
•: Disease or Syndrome

A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.

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Seizure

MedGen UID:: 20693
•Concept ID:: C0036572
•: Sign or Symptom

A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

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Global developmental delay

MedGen UID:: 107838
•Concept ID:: C0557874
•: Finding

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

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Intellectual disability

MedGen UID:: 811461
•Concept ID:: C3714756
•: Mental or Behavioral Dysfunction

Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.

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Scoliosis

MedGen UID:: 11348
•Concept ID:: C0036439
•: Disease or Syndrome

The presence of an abnormal lateral curvature of the spine.

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Neonatal hypotonia

MedGen UID:: 412209
•Concept ID:: C2267233
•: Disease or Syndrome

Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.

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Prominent forehead

MedGen UID:: 373291
•Concept ID:: C1837260
•: Finding

Forward prominence of the entire forehead, due to protrusion of the frontal bone.

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Wide nasal bridge

MedGen UID:: 341441
•Concept ID:: C1849367
•: Finding

Increased breadth of the nasal bridge (and with it, the nasal root).

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Hypertelorism

MedGen UID:: 9373
•Concept ID:: C0020534
•: Finding

Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

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Abnormality of head or neck
- Prominent forehead
- Wide nasal bridge
Abnormality of the digestive system
- Feeding difficulties in infancy
Abnormality of the eye
- Hypertelorism
Abnormality of the musculoskeletal system
- Neonatal hypotonia
- Scoliosis
Abnormality of the nervous system
Ear malformation
- Sensorineural hearing loss disorder

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVFG syndrome
- CROGVAarskog syndrome
- CROGVFG syndrome 1
- CROGVFG syndrome 2
- CROGVFG syndrome 3
- CROGVFG syndrome 4
- CROGVFG syndrome 5

FG syndrome
- FG syndrome 4

Recent clinical studies

Diagnosis

A novel missense variant in the CASK gene causes intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia.

Wu S, Jiang C, Li J, Zhang G, Shen Y, Wang J
BMC Med Genomics 2022 Jun 6;15(1):127. doi: 10.1186/s12920-022-01275-z. PMID: 35668446 Free PMC Article

A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.

Dunn P, Prigatano GP, Szelinger S, Roth J, Siniard AL, Claasen AM, Richholt RF, De Both M, Corneveaux JJ, Moskowitz AM, Balak C, Piras IS, Russell M, Courtright AL, Belnap N, Rangasamy S, Ramsey K, Opitz JM, Craig DW, Narayanan V, Huentelman MJ, Schrauwen I
Am J Med Genet A 2017 Mar;173(3):611-617. Epub 2017 Jan 31 doi: 10.1002/ajmg.a.38069. PMID: 28139025

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