Failure to thrive

Inadequate weight gain (or weight loss) over time, generally weight-for-age below the 5th percentile, weight-for-length below the 5th percentile, or a sustained drop crossing two major percentile lines. "FTT" is a chief complaint, not a diagnosis. Most pediatric FTT is multifactorial and non-genetic (feeding mechanics, psychosocial, GI losses, occult infection). The genetic angle comes in after the basics have been worked through, or earlier when the pattern of growth, dysmorphism, or a specific lab points toward a particular syndrome.

The first split: inadequate intake, inadequate absorption, or inadequate utilization?

1. Inadequate intake: feeding mechanics (cleft, micrognathia, Pierre Robin), neurologic (poor suck, hypotonia), psychosocial.
2. Inadequate absorption / GI loss: cystic fibrosis, celiac disease, IBD, milk-protein allergy, congenital diarrhea syndromes.
3. Inadequate utilization / excessive demand: metabolic disease, chronic infection, congenital heart disease, renal tubular acidosis.

Then the genetic differential layers in by what else is on the exam:

• Symmetric proportional growth failure with no dysmorphism → think nutritional/medical/psychosocial first.
• Asymmetric or syndromic features → chromosomal, microdeletion, RASopathy, imprinting disorder.
• Disproportionate (short limbs, short trunk) → skeletal dysplasia.
• Episodic decompensation, hypoglycemia, acidosis → inborn errors of metabolism.
• Salt-wasting / virilization / hyperpigmentation in the newborn → congenital adrenal hyperplasia (life-threatening; cannot miss).

Must-not-miss treatable diagnoses

• Congenital adrenal hyperplasia (CYP21A2, others): salt-wasting form presents in the second week with vomiting, dehydration, hyponatremia, hyperkalemia, and shock. The non-salt-wasting forms present with poor weight gain, ambiguous genitalia (46,XX), or virilization. Newborn screening (17-OHP) catches most but not all. Test early; missing it kills.
• Cystic fibrosis (CFTR): meconium ileus in newborns; FTT with steatorrhea and recurrent pulmonary infection in older infants. Sweat chloride > 60 mmol/L confirms.
• Turner syndrome (45,X or mosaic): short stature is the most consistent feature and may dominate before puberty. ALWAYS karyotype a short girl with growth failure, even without classic features (webbed neck, cardiac, lymphedema) since mosaic 45,X can be subtle.
• Celiac disease: TTG-IgA + total IgA, irritable child after gluten introduction.

Chromosomal and microdeletion syndromes

• Russell-Silver syndrome (H19 hypomethylation at 11p15, mUPD7): asymmetric IUGR + relative macrocephaly + clinodactyly + triangular face + hemihypotrophy. Postnatal growth failure persists.
• Down syndrome (trisomy 21): mild FTT common, exacerbated by cardiac disease or AVSD-related heart failure.
• Williams syndrome (7q11.23 del): FTT in infancy + transient hypercalcemia + supravalvular AS + characteristic face + cocktail-party personality.
• 22q11.2 deletion syndrome: FTT + cardiac (interrupted arch, TOF) + cleft palate + immune.

RASopathies

• Noonan syndrome (PTPN11, SOS1, RAF1, others): short stature, FTT (often with severe feeding difficulties in infancy), pulmonic stenosis or HCM, ptosis, low-set posteriorly rotated ears, webbed neck.
• Costello syndrome (HRAS) and cardiofaciocutaneous syndrome (BRAF, MEK1, MEK2): severe failure to thrive in infancy is characteristic; feeding tubes often needed.

Skeletal dysplasias (disproportionate growth failure)

A skeletal survey is the test. If upper-to-lower segment ratio is high or arm span doesn't match length, the differential is structural, not nutritional.

• Achondroplasia and hypochondroplasia (FGFR3): rhizomelic short limbs, macrocephaly, midface retrusion.
• Hypophosphatasia (ALPL): low alkaline phosphatase + bone fragility + tooth loss. Treatable with asfotase alfa, so it's a must-not-miss.
• See short stature for the broader skeletal differential.

Inborn errors of metabolism

Most metabolic disease produces episodic decompensation, not steady FTT, but persistent FTT is the dominant feature of:

• GSD type Ia: massive hepatomegaly + fasting hypoglycemia + lactic acidosis; growth failure is striking.
• Mitochondrial disease, organic acidemias, FAOD: when chronic and partially compensated, the only visible sign may be poor growth and intermittent illness.
• Renal tubular acidosis (proximal, distal, Fanconi syndromes from cystinosis, Lowe syndrome, Dent disease): non-anion-gap acidosis, hypokalemia, rickets.

Endocrine

• Growth hormone deficiency (isolated or panhypopituitarism, sometimes with septo-optic dysplasia): postnatal-onset proportional growth failure with low IGF-1.
• Congenital hypothyroidism: caught on newborn screening; missed forms present with constipation, lethargy, large fontanelle, coarse facies.

Mechanical (intake)

• Cleft lip/palate, Pierre Robin sequence, micrognathia: see cleft lip and palate.

A tiered approach. Most non-genetic causes are excluded by step 2; step 3 is where genetics enters.

1. History and growth-curve review. Plot every weight. Is this a child who always tracked low, or one who fell off?
2. Basic workup: CBC, CMP (looking for acidosis, electrolyte abnormalities), TSH, urinalysis, sweat chloride (CF), TTG-IgA + total IgA (celiac), HIV (if risk), tuberculin testing as appropriate.
3. Endocrine: IGF-1, IGFBP-3, 17-OHP if not on newborn screen panel.
4. Karyotype in any short girl (Turner is the diagnosis you never want to miss because cardiac surveillance changes everything).
5. Chromosomal microarray if dysmorphic, developmentally delayed, or multiple anomalies.
6. Skeletal survey if disproportionate.
7. Methylation testing for Russell-Silver / Beckwith-Wiedemann if growth pattern is suggestive.
8. Metabolic workup (plasma amino acids, urine organic acids, acylcarnitine profile, ammonia, lactate) if episodic illness or biochemical clues.
9. Targeted gene panel or exome if syndrome is strongly suspected but specific gene unclear.