Short stature

Height below the 3rd percentile (or more than 2 SD below the mean) for age and sex, OR a height velocity that has crossed downward through two major percentile lines after age 2. Most pediatric short stature is constitutional or familial; the genetic differential becomes important when growth is disproportionate, when dysmorphism is present, or when a chromosomal or single-gene syndrome is suggested by the pattern.

The single most discriminating maneuver is to ask proportionate or disproportionate, using:

• Upper-to-lower segment ratio (US:LS): pubis to crown, divided by pubis to floor. Normal ratio decreases with age (1.7 at birth → 1.0 by age 7). A ratio above the age-norm = short legs (rhizomelic/mesomelic dysplasia). Below the age-norm = short trunk (spondyloepiphyseal dysplasia).
• Arm span vs height: arm span should approximate height after age 8. A short arm span suggests rhizomelic shortening; a long arm span (relative to height) suggests short trunk.
• Sitting height (an alternative to US:LS).

The split organizes the differential:

1. Disproportionate short stature → skeletal dysplasia. Order a skeletal survey.
2. Proportionate short stature → chromosomal (Turner first in girls), endocrine, nutritional/chronic disease, IUGR/imprinting, idiopathic.

Disproportionate (skeletal dysplasia): order a skeletal survey

• Achondroplasia (FGFR3, AD, ~80% de novo): rhizomelic short limbs + macrocephaly + frontal bossing + midface retrusion + trident hand + characteristic "champagne-glass" pelvis. The classic skeletal dysplasia phenotype.
• Hypochondroplasia (FGFR3): milder achondroplasia phenotype; often not recognized until 2-3 years of age.
• Spondyloepiphyseal dysplasia congenita (SEDc) (COL2A1): short trunk + short stature + myopia + retinal detachment + cleft palate + odontoid hypoplasia (atlantoaxial instability is a surgical issue).
• Pseudoachondroplasia (COMP): looks normal at birth, growth slows in early childhood, short limbs + waddling gait + joint hypermobility + normal-sized head (distinguishes from achondroplasia).
• Hypophosphatasia (ALPL): low alkaline phosphatase + bone fragility + premature loss of deciduous teeth + rickets-like skeletal findings. Treatable with asfotase alfa, so a must-not-miss.
• Leri-Weill dyschondrosteosis (SHOX haploinsufficiency): mesomelic shortening (short forearms/legs) + Madelung deformity of the wrist + short stature. SHOX is on the pseudoautosomal region; haploinsufficiency is part of Turner syndrome's short stature.

Proportionate (chromosomal)

• Turner syndrome (45,X or mosaic): always check karyotype in any short girl, regardless of how subtle the rest of the exam is. Short stature is the most consistent feature and may be the only one. Mosaic Turner can present with isolated short stature without webbed neck, lymphedema, or coarctation. Pediatric endocrinology starts growth hormone early; cardiology surveillance is lifelong.
• Noonan syndrome (PTPN11, SOS1, RAF1, others): short stature + pulmonic stenosis or HCM + ptosis + low-set posteriorly rotated ears + webbed neck. The "Turner-like" male; sometimes called the male phenocopy historically.
• Down syndrome, Williams, Prader-Willi, and many microdeletion syndromes have short stature as one component.

Proportionate (endocrine)

• Growth hormone deficiency (isolated or part of hypopituitarism): postnatal-onset proportional growth failure with low IGF-1 and low IGFBP-3. Provocative GH testing confirms.
• Hypothyroidism: cold intolerance + constipation + bradycardia + delayed bone age. TSH on every short child.
• Cushing syndrome (endogenous or iatrogenic): weight gain with linear growth arrest + buffalo hump + striae.
• Pseudohypoparathyroidism (Albright hereditary osteodystrophy): short stature + brachydactyly (especially shortened 4th metacarpal) + round face + obesity + hypocalcemia + hyperphosphatemia.

Proportionate (IUGR / imprinting)

• Russell-Silver syndrome (H19 hypomethylation at 11p15, mUPD7): IUGR + relative macrocephaly + triangular face + clinodactyly + hemihypotrophy + feeding difficulties + persistent postnatal growth failure. Methylation testing is diagnostic.
• Other small-for-gestational-age (SGA) infants who don't catch up by age 2 may benefit from GH; need to look hard for an imprinting or chromosomal etiology before labeling "idiopathic."

Proportionate (nutritional or chronic disease)

The "non-genetic" categories you must rule out before invoking a syndrome.

• Celiac disease: TTG-IgA + total IgA in every workup.
• Inflammatory bowel disease: CBC, ESR/CRP, albumin, stool calprotectin.
• Renal tubular acidosis, chronic kidney disease: electrolytes, urinalysis, creatinine.
• Cystic fibrosis: sweat chloride.

Constitutional delay of growth and puberty

The classic "late bloomer." Normal height velocity, delayed bone age, family history of delayed puberty. Diagnosis of exclusion in older children with otherwise normal exam.

A pragmatic opening sequence:

1. Plot the growth curve and calculate height velocity. Crossing percentiles is more concerning than tracking below 3rd.
2. Measure parents. Mid-parental height predicts genetic target; height below 1.6 SD of target deserves investigation.
3. Calculate US:LS ratio, arm span, sitting height. Proportionate or disproportionate?
4. Bone age (left hand and wrist radiograph): delayed in constitutional delay and hypothyroidism, advanced in precocious puberty, severely delayed in GH deficiency.
5. Karyotype in any short girl (Turner, often mosaic, often subtle).
6. Skeletal survey if disproportionate or if dysplasia suspected on exam.
7. Endocrine panel: TSH, free T4, IGF-1, IGFBP-3, morning cortisol if pituitary concern. Provocative GH testing in selected cases.
8. Celiac screen (TTG-IgA + total IgA), CBC, CMP, urinalysis to rule out chronic disease.
9. SHOX testing if Leri-Weill features (Madelung deformity, mesomelic shortening).
10. Methylation testing if Russell-Silver clinically suspected.
11. Chromosomal microarray if developmental delay, dysmorphism, or multiple anomalies accompany short stature.
12. Targeted gene panel or exome if a specific skeletal dysplasia is suspected on survey but the radiologic phenotype is ambiguous.