short stature and poor growth - westchester health pediatrics
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Short Stature and Poor Growth
Joan Di Martino-Nardi, M.D.Westchester Health Associates
PediatricsMarch 31, 2016
Joan Di Martino-Nardi, M.D.
• InvestigatoroNovoNordisk
• Speaker’s BureauoNovoNordiskoGenentech
Objectives • Review Normal growth
• Identify the children who should be evaluated for short stature or poor growth
• Understand the causes of short stature/poor growth
• Review Growth Hormone and IGF-1 physiology
• Outline Evaluation
Height Prediction-Based upon bone age andHeight at the time bone age is obtained
-Bayley-Pinneau method is the most accurate method (± 2 inches)
(plot height for bone age)
Height for bone age
Predicted height
Height for Chronological age
Genetic Potential: Target HeightHeight Prediction should be = Target HeightTarget height = Midparental height ± 5 cm ( 2
inches) Midparental height for Males: {mother’s height + 5 inches} + father’s height Midparental height for Females {father’s height – 5 inches} + mother’s height 2 *13 cm=5 inches
Who Should Be Evaluated?• Height < 3rd percentile (10% have pathology)*
• Height velocity < 2 inches (5 cm) per year--Downward crossing of percentiles on growth chart after age 2-3 years of age
• Height prediction below genetic potential or below the Target height.
• “Sick” children who do not grow as expected after initiation of therapy for their “illness”
*Lacey KA, Parkin JM. Causes of short stature. A community study of children in Newcastle-uponTyne. Lancet 1974; 1:42-25.
Causes of Short Stature or Poor Growth
• Normal oFamilial short statureoConstitutional short stature
• “delayed growth and development”• “late bloomers”
Familial Short Stature• Family history of short stature• Normal age of onset of puberty• All lab tests are normal (ie. Healthy)• Bone age is ~the same as the chronological age• Predicted height and adult final height are
consistent with genetic potential or Target height
Familial Short Stature
Constitutional Growth Deley• “slow growers” or “late bloomers”
• Family history of delayed puberty
• Normal growth velocity until 10-14 years of age for boys or 8-10 years for girls
• Delayed puberty: height deviates from growth curve at ~10-14 years
• Labs: wnl (i.e. healthy)
• Bone age delay: 2-4 years
• Later “catch-up growth”
• Normal height in adulthood: lower end of the normal height for their family (short for their families)
Growth Velocity Curve--Boys
Early PubertyDelayed puberty
Constitutional delay of growth
and development
Constitutional Delay of Growth: Expected versus Final Adult Height
La Franchi S, Hanna CE, Mandel, SH Pediatrics, 1991; 87;82-87
To Grow Normally,A child needs to be
….healthy ……..fed ………..and loved
Causes of Short Stature or Poor Growth
o Fed• Nutritional*• Low birth weight or length
(SGA=small for gestational age)
o Loved• Psychosocial
o Healthy• Endocrine
o Hypothyroidismo Abnormalities of GH-IGF-1
axis• Chromosome defects: Turner’s
Syndrome, Noonan’s Syndrome• Bone development disorders
o SHOX deficiency• Metabolic• Chronic diseases and their
therapies• Birth defects
Pathologic cause of short statureWe as providers need to confirm the child
is…
Nutritional Growth Retardation (NGR)• Real illness
o Inflammatory bowel diseaseo Celiac diseaseo Cystic fibrosiso Cardiac, renal, HIV
• Poverty related malnutrition-worldwide• Self-restricted nutrient intake in suburban upper middle
class—USAo Patients have adapted to their suboptimal nutritional intake
and may not appear wasted
How Is SGA Defined?Usher and McLean Growth
Curves
Catch-up Growth in Children Born SGA
Noonan Syndrome: What Physicians Need to Know JA Noonan, MD, AE Roberts, MD, JDahlgren, PhD
Clinical Review, Medscape Pediatrics, September 2007
SHOX deficiency
Photo
Phenotype of GH receptor deficiency. Brothers, ages 3 7/12 (left) and 1 9/12 (right), were homozygous for nonsense mutations (R43X) in the GH receptor gene. Their heights were -7.2 and -5 SD below mean for age, respectively. A random blood sample obtained on the younger showed low levels of IGF-I (6 ng/ml; normal 17-248) and IGFBP-3 (0.2 mg/l; normal 0.9-4.1) in the face of moderately elevated circulating GH concentration (19.8 ng/ml). They weretreated with recombinant IGF-I for 11 years. During this time they grew 4.6 cm/yr on average, a growth velocity slightly lower than that of normal children, but greater than that expected, in untreated patients with this diagnosis, [3]. Photographs and baseline laboratory data from Rosenbloom et al. [42]. Used with permission.
Rosenbloom AL. J Pediatr Endocrinol Metab 1995;8:159-65.
Growth Hormone Deficiency• Isolated• Associated with multiple pituitary hormone deficiencies
o TSH, LH, FSH, ACTH, Vasopressin• Congenital
o malformations/inherited genetic disorders• Acquired
o tumors, head trauma, radiation therapyAnything affecting CNS can result in GHD
The GH-IGF-IGFBP Axis
Transport
CellularIGFBP
ReceptorsRXR-Nuclear actions
NuclearReceptors
Cell surfaceBP-receptors
---IGFBPsTypeIGF Receptor
Ia
b
Survival &MitogenesisVia IRS-1 -- Akt, MAPK and other pathways
IGF-I
IGF-II
Insulin
GH
Differentiation, growth, aging, metabolism & carcinogenesis
ALS
150 kDa complex
IGFBP-1 IGFBP-2 IGFBP-3 IGFBP-4 IGFBP-5 IGFBP-6
TypeIGF Receptor
II
IGF2 binding
Mannose-6-phosphate bindingRetinoid binding
Growthinhibition
GH
Cohen P. Horm Res 2006; 65 Suppl 1:p. 5.
Evaluation of Short Stature History
• Birth historyo Mother’s pregnancy
• Illness, toxins, alcohol/drugs, • Peri-natal events
o Birth weight and length • Medical history
o ROS (signs of chronic disease)o Medication history
• Family history o Height, “late bloomers” and pubertal timingo Height of parents to calculate mid-parental heighto Significant “life” events (psychosocial)
• Growth curves
Physical Exam• Height and weight• Head circumference• Body proportions (skeletal dysplasia?)
o Arm spano Upper/segment ratio
• Dysmorphic features: metacarpals, midline craniofacial defects, Madelung deformity, cubitus valgus
• Pubertal status • Scoliosis • Body proportions• Signs of chronic illness: pallor, dry skin, poor dentition
Evaluation• CBC• ESR or C-Reactive Protein• Biochemical profile• T4, TSH. Anti-thyroglobulin and thyroid peroxidase antibodies• Celiac Screen• IGF-1/IGFBP-3• Bone Age (for height prediction)• Genetic tests: Karyotype (girls); SHOX and• Skeletal survey if hypochondoplasia suspected (i.e.abnormal body
proportions)• Growth Hormone testing• MRI of the pituitary with and without gadolinium for children with
growth hormone deficiency
Psychosocial Consequences of Short Stature
• Overall : Most children have normal psychosocial function
• Short stature may be a risk factor for psychosocial problems*o Social immaturityo Infantilizationo Low self esteemo Being bullied
*May be a function of several risk factors including parental attitudes and prevailing cultural opinions
*Clinic-based populations may display greater psychosocial dysfunction
From Lawson Wilkins Consensus Statement on ISS JCEM epub Sept 2008
Short Stature: The Social Problem
Prejudice is pervasive • “Feisty” refers to short people• “Distinguished” used to describe a tall person• “Look up to”; “look down upon”• “how tall are you?” vs. “what is your height?”• “Short People (Randy Newman)—”grubby little fingers,
dirty little minds, with no reason to live”• Etc……..
“The Height of Your Life” by Ralph Keyes
"Children have a short time to grow and a lifetime to live with the results." ©
Major Aspects of Growth In Children MAGIC FOUNDATION
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