Children with Growth Problems: When to Assess for a Genetic Cause? Carlos A. Bacino, M.D Dept. of Molecular and Human Genetics Baylor College of Medicine and Texas Children’s Hospital Houston, Texas, USA Growth Deficiency • Definition: Height below the normal relative to other children of the same sex, age and ethnic background • Height below the 3rd percentile and ¯ growth velocity Growth Charts • Growth charts used since 1977 • Cross-sectional data of primarily white, formula-fed, middle class infants from southwestern Ohio later adopted by the WHO • WHO growth standards to monitor age 0-2 years • CDC growth charts for age > 2 years in the US. • Introduces BMI • Disease related growth curves • Turner syndrome, achondroplasia Fuqua, J. S., & Lee, P. a. (2014). Lawson Wilkins: portrait of a pioneer. International Journal of Pediatric Endocrinology, 2014(Suppl 1 Remembering Doctor Lawson Wilkins: a pioneer of pediatric endocrinology), I1. 2-20 years – CDC Growth Curves Male Female • Based on US population studies Growth Deficiency • Normal growth is the expression of many factors: • Hormonal • Environmental and psychosocial • Nutrition • Genetic • Metabolic Diseases that alter growth are quite diverse. Adequate linear growth is a good evidence of health Growth Deficiency A. Constitutional delay & growth of adolescence: 1. Normal birth weight and after 6 months slows down to parallel below 5th centile. 2. Normal growth rate with delayed bone age. 3. Late puberty. B. Familial Short Stature: short parents, normal growth velocity, and normal bone age (height is concordant with mid parental percentile) C. Pathologic Growth Failure (hypothyroidism) Define Short Stature - Rule of 2’s • > 2 standard deviations below the mean (or < 3rd percentile) • > 2 SD below mid-parental height • Low growth velocity, falling > 2 SD Murray, P. G., Clayton, P. E., & Chernausek, S. D. (2018). A genetic approach to evaluation of short stature of undetermined cause. The Lancet Diabetes and Endocrinology, 6(7), 564–574. How to evaluate short stature? 1. Is the patient short on the growth chart? Percentile/z-score /proportionate 2. Growth velocity abnormal? 3. Symptoms, medical history? 4. Genetic condition? Familial(heights)? Chronic diseases? 5. Other pituitary functions? 6. Growth Factors (IGF-1 and IGFBP3)? Peak GH? If done, was it primed? Clinical Evaluation: Other Measurements • Arm span (normally equals the height or 5-6 cm longer) • Measure lower segment (from symphysis pubis to heel) and ratio between upper and lower segments: US/LS ratio Laboratory studies • Electrolytes and chemistries • CBC • Urinalysis ++ • Ca , PO4 , alkaline phosphatase, Vitamin D levels • Thyroid function tests • Labs: IGF-1 (somatomedin C), IGFBP3 (also other pituitary markers) • Growth Hormone Stimulation Test Laboratory studies • Carotene levels • Transglutaminase • Antigliadin antibodies • X-rays: bone age, lateral skull (pituitary) • MRI Pituitary w/ and w/o contrast • Full skeletal survey • Chromosomes • Chromosome microarray • Gene panels Bone age – Greulich and Pyle • Popular method • Developed in the US between 1931-1942, updated 1959 • Series of radiographic standards of healthy white children • Males: 31 standards covering 0-19 years of age • Females: 27 standard covering 0-18 years of age • Does not apply accurately to all populations, assumes uniform skeletal maturation • Bone age generally determined by ‘best fit’ • Can be approximated between 2 standards • Appropriate if within 2 standard deviations of chronological age • Standard deviations vary by chronological age and gender, used to predict adult height Delayed Bone Age Advanced Bone Age Endocrine Endocrine • Hypothyroidism • Precocious puberty • GH deficiency • Premature adrenarche • Hypogonadism • Congenital Adrenal Hyperplasia • Corticosteroid excess (untreated) • Hyperthyroidism Non-Endocrine Non-Endocrine • Undernutrition: primary or • Obesity secondary to chronic disease • Constitutional Tall Stature • Rickets • Syndromes: Sotos, Beckwith- • Trisomy (21, 18) Wiedemann Syndrome, Marshall- • Russell Silver Syndrome Smith Syndrome De Sanctis V et al. Hand X-ray in pediatric endocrinology: Skeletal age assessment and beyond. Indian J Endocrinol Metab 2014 Gilsanz V et al. Hand Bone Age: A Digital Atlas of Skeletal Maturity. eBook, Springer 2005 Growth Deficiency Disorders Common Genetic Syndromes Presenting with Short Stature • Rickets • Hypothyroidism • Turner Syndrome • Noonan Syndrome • Russell-Silver Syndrome • Skeletal Dysplasias: - Achondroplasia Rickets Hypothyroidism Delayed bone age Decreased linear growth Delayed dentition T4 low TSH ­ Growth Hormone Deficiency • Short stature • Poor linear growth rate • Delayed bone age • Chubby • Hypoglycemia, small penis in males - Lack of proper GH production after argininine stimulation - ¯ IGF-BP3 - ¯ GH - ¯ IGF-1 (formerly somatomedin-C Turner Syndrome - Clinical Features • Incidence 1/10,000 females • Short stature, mild IUGR, linear growth declines in velocity starting from age 3 years • Short metacarpals, scoliosis, Madelung deformity • Short, wide and webbed neck, low posterior hairline, rotated ears • Edema of the hands and feet, nail dysplasia • Pigmented nevi Turner Syndrome - Clinical Features • Gonadal failure, streak gonads, infertility and hypogenitalism, hypoplastic uterus • Risk higher for ovarian tumors • Horseshoe kidneys • Heart: aortic coarctation • Endocrine: hypothyroidism , Hashimoto thyroiditis Turner Syndrome - Clinical Features • Webbed neck • Protruding ears Turner Syndrome - Clinical Features • Edema of the hands and feet Noonan Syndrome Short stature Neck webbing, short broad neck, cystic hygroma Pectus carinatum Hypertelorism Downslanting palpebral fissures Low set hairline Triangular facies Low set ears Noonan Syndrome • Heart disease, right heart abnormalities: • Valvular pulmonic stenosis • Right ventricular hypertrophy and hypertrophic cardiomyopathy • Hematologic: factor XI deficiency • Autosomal dominant • 50% caused by mutations in PTPN11 • SOS1 gene 10% • KRAS1 gene < than 5% • RAF1 gene 3-17% Russell-Silver Syndrome • IUGR • Low birth weight and height often 3SD below the mean • Head circumference sparing • Asymmetric growth • Triangular facies • Small mouth • 5th finger shortening • Delayed in gross motor milestones Russell-Silver Syndrome • Tendency to develop hypoglycemia from 1 to 2 years of age • Short stature with final height closer to 5 feet • Treatment: GH? • Etiology: • Maternal UPD 7 (10%). There are 2 imprinteD genes on chromosome 7 implicated: GRB10 and MEST • Epigenetic defect on chromosome 11 = epimutations (loss of paternal methylation on H19) and maternal duplications of 11p15 in 35% of patients. Skeletal Dysplasias • Genetic disorders of skeletal development are a large (>456), extremely heterogeneous group of conditions that may present anytime from the prenatal period to adult life • Prognosis ranges from death shortly after birth to survival into adulthood with normal intellectual development Achondroplasia • Autosomal Dominant Inheritance, 80% are new mutations • Advanced paternal age • Incidence 1/20,000 • Gene mutated is FGFR3, at nucleotide 1138 in the trans-membrane (TM) domain • FGFR3 inhibit bone growth. Achondroplasia appears to be the result of “a gain of function mutation” suggesting that receptor downregulates FGF signal transduction Achondroplasia: clinical features • Macrocephaly, frontal bossing, midface hypoplasia • Lordosis • Trident hands • Short stature, rhizomelic shortening Vosoritide: Annualized Growth Velocity (Phase 2) • Doses of 15ug/kg/day and up were associated with sustained increase in height velocity C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. Savarirayan R, et al. N Engl J Med. 2019. PMID: 31269546 Phase 3 Vosoritide Trial • 121 ACH individuals randomized placebo drug for the first year • 52 weeks clinical trial • Vosoritide 15 mcg per kg SC had increased in AGV • No clinically significant side effects • No improvement or worsening of disproportion • AGV averaged 1.57 cm per year (0.90-1.84 cm) Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Savarirayan R, et al. Lancet. 2020. PMID: 32891212 Conclusions Short stature is due to multifactorial genetic and environmental factors Address patients’ height, growth rate (AGV), parental heights and familial genetic patterns Recognize chronic conditions Recognize nutritional factors Bone dysplasias are the result of mutations in genes expressed in joints and bone tissues.