• Clinical science

Rare inherited syndromes


This card provides an overview of inherited symptom complexes that occur rarely in the general population. These syndromes are caused by inherited genetic defects, which occur either due to chromosomal aberrations or autosomal/sex-linked traits. The presentation differs for each syndrome, with most features arising from developmental, functional, or structural anomalies of various organs. Diagnosis can be confirmed with the help of molecular genetic detection, fluorescence in situ hybridization (FISH), or other genetic/chromosomal studies. Treatment is usually symptomatic.

Fragile X syndrome

Fragile X → X-tra large → big ears, testes, face


Prader-Willi syndrome and Angelman syndrome

Prader misses his Papa: In Prader syndrome, the Paternal allele is mutated/deleted. In AngelMan syndrome, the Maternal allele is mutated/deleted.

Prader-Willi syndrome

Angelman syndrome

  • Clinical features
    • Delayed mental development and acquisition of motor skills in infants and young children
    • In more than 80% of cases, pronounced epileptic seizures
    • Microcephaly
    • Ataxia, tremulous movements of the limbs
    • Truncal hypotonia, limb hypertonia, hyperreflexia
    • Difficulty sleeping
    • Intellectual disability
    • Characteristic happy demeanor with frequent laughing (inappropriate laughter)
    • Hyperexcitability, short attention span
    • Fascination with water
  • Treatment
    • No specific treatment
    • Physical, occupational, and speech therapy
    • Antiepileptic drugs (if applicable)
  • Prognosis: Life expectancy is typically normal.


Zellweger syndrome (cerebrohepatorenal syndrome)


Pierre Robin sequence (Pierre Robin syndrome)

  • Definition: : a set of abnormalities causing fetal oral and maxillofacial malformations The term "Pierre Robin syndrome" is actually a misnomer. "Syndrome" implies the occurrence of multiple symptoms simultaneously, all of which have the same underlying cause. "Pierre Robin sequence" is, therefore, more accurate, as the condition is a sequence of various morphologic defects that are correlated with one another, the exact etiopathogenesis of which may vary. Some people have the features of Pierre Robin sequence as part of a syndrome that affects other organs and tissues in the body, such as campomelic dysplasia. When Pierre Robin sequence occurs by itself, it is described as nonsyndromic or isolated.
  • Clinical features
    • Cleft palate
    • Glossoptosis with possible complications such as acute respiratory distress and aspiration
    • Mandibular retrognathia; or micrognathia
    • Possible intellectual disability
  • Diagnosis: fluorescence in situ hybridization (FISH)
  • Treatment
    • If moderate dyspnea: symptomatic treatment
      • Noninvasive ventilation
      • Supervision and assistance while eating
    • If severe dyspnea: surgical correction
      • Special interventions for long-term correction
      • In cases of acute life-threatening respiratory distress → tracheostomy


Cri-du-chat syndrome (cat cry syndrome)

  • Definition: rare syndrome caused by a chromosome 5 aberration.
  • Epidemiology: sex distribution: > (2:1)
  • Etiology: microdeletion of the short arm at chromosome 5 (46,XX or XY, 5p‑).
  • Clinical features
    • Cat-like, high-pitched crying in affected infants
    • Cardiac abnormalities (VSD)
    • Intellectual disability (moderate to severe)
    • Single palmar crease
    • Dysmorphic facial features (e.g., microcephaly, epicanthal folds, broad nasal bridge, downward-slanting palpebral fissures, moon facies, widely spaced eyes)
    • Skeletal abnormalities
  • Treatment
    • Symptomatic treatment
    • Early psychological and physical assistance
  • Prognosis: A normal life expectancy is possible, but depends on the accompanying symptoms and therapeutic assistance.


Rett syndrome

  • Definition: X-linked disorder with progressive loss of intelligence and cognitive abilities such as language, locomotion, and fine motor skills
  • Etiology: X-linked dominant gene mutation (in methyl-CpG binding protein 2 [MECP2] gene)
    • Usually not an inherited gene defect, but rather a sporadic mutation. The mutated copy of the MECP2 gene is often associated with the paternal allele, as it occurs randomly during spermatogenesis → primarily females are affected
      • Since it is usually a sporadic mutation, individual risk does not increase if relatives are affected.
  • Clinical features
    • Affects females almost exclusively
    • Normal development and then onset between 7–24 months of age
  • Diagnosis: : a combination of typical clinical presentation and gene mutation detection
  • Prognosis: There is not enough data regarding life expectancy beyond the the age of 40, as long-term studies are not available and the disease is fairly rare.

Rett syndrome Regresses: After normal development, loss of targeted hand movements and intellectual and verbal disability occurs!


Williams syndrome

  • Definition: multisystem developmental disorder caused due to deletion at chromosome 7
  • Etiology: microdeletion of the long arm of chromosome 7 (includes a deletion of the elastin gene)
  • Clinical features
    • Characteristic cognitive abnormalities (including intellectual disability, hypersociability, comfort with strangers)
      • Good verbal skills for the degree of intellectual disability
    • Characteristic facial features (“elfin” facies): midfacial hypoplasia, short palpebral fissure, wide forehead, flattened nasal bridge, anteverted nostrils, long philtrum, hypodontia
    • Cardiovascular malformations; (esp. supravalvular aortic stenosis )
    • Hypercalcemia (due to impaired sensitivity to vitamin D)
    • Low muscle tone
    • Hyperacusis, phonophobia
    • Potential malformations and development problems in multiple organ systems
  • Diagnosis: : a combination of typical clinical presentation and gene mutation detection


Rubinstein-Taybi syndrome

  • Definition: inherited syndrome (CREBBP gene mutation ) with characteristic facial dysmorphia
  • Clinical features
    • Typical facial shape: highly arched eyebrows, beaked nose with hypoplastic wing of the nose
    • During infancy: hairy forehead
    • Short stature
    • Broad thumbs and toes
    • Intellectual disability
  • Prognosis: usually poor; infants born with this disorder usually survive only to early childhood


Smith-Lemli-Opitz syndrome


Albright hereditary osteodystrophy (Martin-Albright syndrome)


Noonan syndrome


Silver-Russell syndrome

  • Definition: rare, sporadic syndrome associated with intrauterine growth retardation
  • Clinical features
    • Infant length
    • Relative macrocephaly
    • Dysmorphic facial features: asymmetric triangular face with a high forehead and drooping labial commissures
    • Clinodactyly (crooked finger)
    • Normal or mildly impaired cognitive development