Short stature

Short stature (dwarfism) in children is defined as a height that is at least two standard deviations (SDs) below the mean for children of the same age and sex. In adults, the condition is commonly defined as a height of 5 ft 1 in (155 cm) or less in men and 4 ft 10 in (147 cm) or less in women. Nonpathological variant short stature can be classified into three types: familial short stature (inherited short stature), constitutional delay of growth and puberty (an inherited pattern of short stature during childhood that is followed by a growth spurt during puberty, typically resulting in normal adult height), and idiopathic short stature (short stature in the absence of any metabolic, endocrine, or other diagnosis). These types of short stature are most often normal variants of growth and rarely affect a child's development beyond longitudinal growth. The pathological causes of short stature are diverse and include psychosocial circumstances as well as a variety of genetic, endocrine, and metabolic disorders, which may affect a child's development in other ways than longitudinal growth. Further diagnostic testing is indicated if a child's growth is less than what might be expected given the average height of the parents. An x-ray of the left hand and wrist are made to determine bone age (skeletal age), based on which the adult size of the child can be predicted. Laboratory testing can help rule out any underlying condition. Treatment is rarely indicated in nonpathological short stature (e.g., if short stature does not represent a disability to the patient), while pathological short stature is treated according to the underlying condition and usually involves growth hormone supplementation.

• Short stature (dwarfism)
  • Children: height of > 2 SDs below the mean for children of the same age, sex, and similar genetic background
  • Adults: height of ≤ 4 ft 10 in (147 cm) for women and ≤ 5 ft 1 in (155 cm) for men ^[1]
• Proportionate short stature
  • Limbs proportionate to trunk
  • Seen in most cases of familial short stature
• Disproportionate short stature
  • Limbs disproportionately short compared to trunk
  • Seen mostly in cases of skeletal dysplasia
• Growth failure: growth rate below the rate considered appropriate for sex and age.

Short stature can have a variety of genetic, systemic, and psychosocial causes.

• Genetic causes include:
  • Constitutional growth delay
  • Laron syndrome
  • Turner syndrome
• Systemic causes include:
  • Congenital hypothyrodism
  • GH deficiencies
  • Glucocorticoid excess
• Psychosocial causes include:
  • Maternal substance use (e.g., alcohol)
  • Psychosocial short stature
  • Psychiatric conditions (e.g., anorexia nervosa)

Patient history

• Physical examination findings
• Growth rate
• Family history of short stature
• Midparental height (target height)
  • ♀ = [mother's height in cm + (father's height in cm - 13)]/2
  • ♂ = [father's height in cm + (mother's height in cm + 13)]/2

Laboratory tests

• CBC, differential blood count, ESR
• Thyroid function tests (see “Hypothyroidism”)
• Renal function tests and urinalysis (in case of CKD and associated renal osteodystrophy)
• Screening for GH deficiency (see “Hypopituitarism”)
• Hormone profile (LH, FSH, estrogen/testosterone) for puberty status assessment
• Karyotyping

Imaging tests

• X-ray: used to determine an individual's bone age and height by comparing their x-ray images of the left hand and wrist to those displayed in the standard bone development atlas
• Cranial MRI: in suspicion of hypothalamic or pituitary tumors

Management depends on the underlying cause:

• Reassurance that low height is a normal variant (e.g., familial short stature) that does not require treatment
• Discontinuation of growth-inhibiting medication (e.g., glucocorticoids)
• Sex hormone substitution in children with delayed puberty and growth
• GH supplementation in cases of GH deficiency, idiopathic short stature, and Turner syndrome
• Treatment of underlying conditions (see “Causes of short stature” above)

Achondroplasia ^[2]

• Epidemiology
  • Most common type of skeletal dysplasia and of disproportionate short stature
  • 1:15,000–40,000 children affected in the US
• Etiology
  • Gain of function mutation in fibroblast growth factor receptor 3 gene (FGFR3) on chromosome 4
  • New (sporadic) mutations in ∼ 80% of cases ^[3]
  • The probability of new mutations increases with the father's age at the time of conception.
  • Autosomal dominant inheritance in ∼ 20% of cases (homozygosity is lethal) ^[4]
• Pathophysiology
  • Defective FGFR3 → continuous receptor stimulation by FGF → inhibited chondrocyte proliferation → ↓ endochondral ossification → impaired longitudinal bone growth
  • Normal intramembranous ossification of the craniofacial bones → disproportionately large head in relation to the limbs
• Clinical presentation
  • Stature
    • Short stature
    • Average-sized torso
    • Short, plump extremities
  • Craniofacial abnormalities
    • Macrocephaly
    • Prominent brows
    • Midface retrusion
    • Flattening of the nose
    • Middle ear deformation: recurrent otitis media
  • Other skeletal abnormalities
    • Small foramen magnum: compression of the cervical medulla
    • Lumbar lordosis and kyphoscoliosis
    • Spinal canal stenosis: low back and leg pain, paresthesias, dysesthesia, incontinence
    • Small chest wall
  • Normal intellectual development
• Diagnostics
  • Physical examination
  • X-ray findings
    • Lateral skull: frontal prominence, midface hypoplasia
    • Spine: spinal canal stenosis, scoliosis
    • Extremities: short and broad bones
  • Cranial CT/MRI: indicated in patients with signs of cervicomedullary compression
    • Assessment of brain stem compression
    • Measurement of the size of the foramen magnum
• Therapy ^[5]
  • Early administration of growth hormone (between 1–6 years of age)
  • Surgical correction of spinal stenosis, secondary scoliosis, genu varum, brain stem compression

Osteogenesis imperfecta (brittle bone disease)

• Etiology: various genetic defects; most commonly autosomal dominant mutations in COL1A1 or COL1A2 genes ^[6]
• Pathophysiology: ↓ formation of hydrogen and disulfide bonds between type I preprocollagen molecules → ↓ triple helix formation → ↓ synthesis of normal type I collagen → impaired bone matrix formation (osteogenesis)
• Clinical features ^[7][8]
  • Osteogenesis imperfecta type I (the mildest and the most common form)
    • Growth delay
    • Skeletal deformities, brittle bones
    • Bowing of bones and saber shins
    • Fractures during childbirth and recurrently from minimal trauma thereafter
    • Blue sclerae (choroidal veins show through the thin, translucent sclera)
    • Progressive hearing loss due to deformation, fracture, or atrophy of the ossicles
    • Brittle, opalescent teeth (dentinogenesis imperfecta; due to a lack of dentin)
    • Ligamentous laxity and joint hypermobility
  • Osteogenesis imperfecta type II
    • Most severe form; lethal perinatally or within the first year
    • Multiple intrauterine and/or perinatal fractures
    • Underdeveloped lungs and subsequent respiratory problems
• Diagnostics
  • DNA test
  • Ultrasound before birth and radiographic skeletal survey afterward (to visualize fractures, calluses, deformities)
  • Bone or skin biopsy to examine collagen
• Therapy
  • No definitive treatment available
  • Supportive measures: walking aids, wheelchairs, devices to improve patient's mobility and function
  • Bisphosphonates; : increase cortical thickness and decrease the risk of fractures
  • Surgery: to improve mobility and correct the associated skeletal defects

In osteogenesis imperfecta, patients cannot BITE: Bones (recurrent fractures), I for “eye” (blue sclerae), Teeth (dental abnormalities), Ears (hearing loss).

Bone fractures from osteogenesis imperfecta are easily mistaken for signs of child maltreatment.

Campomelic dysplasia

• Definition: a life-threatening disorder characterized by skeletal dysplasia, abnormal sex development, and other congenital defects due to SOX9 gene mutations ^[9][10]
• Etiology
  • SOX9 gene mutations on chromosome 17
  • Autosomal dominant inheritance
  • Results from missense mutations, frameshift mutations, or chromosomal rearrangements
• Clinical features
  • Skeletal abnormalities
    • Bowing of long bones (particularly the legs)
    • Short legs, dislocated hips, clubfeet
    • Underdeveloped shoulder blades
    • Short stature
    • Distinctive facial features (e.g., small chin, prominent eyes, flat face, large head)
    • Pierre Robin sequence (cleft palate, glossoptosis, micrognathia)
  • Abnormalities of the reproductive system
    • In most affected individuals with 46,XY karyotype, the external genitalia will either be ambiguous or female.
    • Internal reproductive organs may not correspond with the external genitalia and individuals can have testes, ovaries, or both.
  • Other defects
    • Life-threatening laryngotracheomalacia
    • Respiratory distress syndrome
    • Hearing loss
• Diagnosis
  • Clinical and radiographic findings
  • Genetic testing
• Treatment
  • Airway protection
  • Surgical repair of congenital anomalies

1. Achondroplasia. https://ghr.nlm.nih.gov/condition/achondroplasia. Updated: February 14, 2017. Accessed: February 16, 2017.
2. Achondroplasia. https://rarediseases.info.nih.gov/diseases/8173/achondroplasia. Updated: November 1, 2019. Accessed: November 13, 2019.
3. Le T, Bhushan V,‎ Sochat M, Chavda Y, Abrams J, Kalani M, Kallianos K, Vaidyanathan V. First Aid for the USMLE Step 1 2019. McGraw-Hill Medical
4. Ireland P, Pacey V, Zankl A, Edwards P, Johnson L, Savarirayan R. Optimal management of complications associated with achondroplasia. Appl Clin Genet. 2014 : p.117-125. doi: 10.2147/tacg.s51485 . | Open in Read by QxMD
5. COL1A1/2-Related Osteogenesis Imperfecta. https://www.ncbi.nlm.nih.gov/books/NBK1295/. Updated: February 14, 2013. Accessed: February 20, 2018.
6. Types of OI. http://www.oif.org/site/PageServer?pagename=AOI_Types. Updated: February 16, 2017. Accessed: February 16, 2017.
7. Fast Facts on Osteogenesis Imperfecta. http://www.oif.org/site/PageServer?pagename=fastfacts. Updated: February 16, 2017. Accessed: February 16, 2017.
8. Campomelic dysplasia. https://rarediseases.org/rare-diseases/campomelic-syndrome/. Updated: January 1, 2007. Accessed: November 19, 2019.
9. Campomelic dysplasia. https://ghr.nlm.nih.gov/condition/campomelic-dysplasia#diagnosis. Updated: November 12, 2019. Accessed: November 19, 2019.
10. Dwarfism. https://www.mayoclinic.org/diseases-conditions/dwarfism/symptoms-causes/syc-20371969. Updated: August 17, 2018. Accessed: November 18, 2019.