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." ©   

                                                                                                

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