Genetic Causes of Growth Disorders

Children often present to pediatricians and pediatric endocrinologists because of abnormal
body growth, including both childhood growth failure and, less commonly, overgrowth.
Sometimes the cause is evident, for example, growth hormone deficiency for growth failure and
growth hormone excess for overgrowth. In other children, the etiology remains unknown despite
extensive evaluation, resulting in the unhelpful diagnosis of severe idiopathic short stature
or tall stature. These conditions are quite heterogeneous, including children with isolated
growth disorders and others who also have other abnormalities such as developmental delay or
a constellation of congenital anomalies (syndromic growth disorders). Some cases of severe
growth disorders have a polygenic inheritance while others appear to be inherited as a
monogenic trait recessive, dominant or X-linked. Because of recent advances in DNA sequencing
technology, it is now feasible to sequence the exome (portion of the genome that encodes gene
exons) in families with monogenic disorders and thereby determine the underlying molecular
etiology.

We therefore propose a study to identify novel genetic causes of idiopathic growth disorders
using whole-exome sequencing. The primary goal of this study is to identify novel causes of
childhood growth disorders in order to improve clinical diagnosis, to provide a more precise
characterization of associated medical problems, prognosis, and response to treatment based
on etiology, and to gain new insights into the regulation of human growth, which may
eventually lead to new therapeutic approaches.

Subjects will include children and adults with a clearly recognizable phenotype that includes
either short stature or tall stature and a pedigree that strongly suggests a monogenic
inheritance. Both syndromic and non-syndromic growth disorders and both proportionate and
disproportionate growth disorders will be included. Affected and unaffected family members
(who have informative meiotic inheritance relationships to the proband or index case) will
also be studied because of their importance for this genetic approach. The phenotype will be
characterized by medical history, physical exam, body measurements, and laboratory
evaluation. Blood and saliva samples will be collected for whole-exome sequencing and single
nucleotide polymorphism (SNP) array analysis. Candidate sequence variants will typically be
verified by Sanger sequencing.

- INCLUSION CRITERIA:

If a subject meets any one of these criteria, he/she will potentially be eligible to
participate:

- Short stature (height less than - 2 SDS), either currently or previously - or

- Tall stature (height greater than + 2 SDS) or

- Bone age delay (greater than 3 years) or

- Bone age advancement (greater than 2.5 years or greater than 1.5 years with short
stature) or

- Predicted adult height < - 2SD

- Growth disorder that was treated promptly, thus maintaining the child s height within
the normal range, e.g. a subject with congenital growth hormone deficiency or multiple
pituitary hormone deficiency of unknown genetic etiology who received growth hormone
treatment beginning in early life or

- Family member of subjects who meet any of the above criteria

In addition, subjects are only eligible, if, the pedigree suggests a monogenic inheritance,
and, in the judgement of the investigators, there is a reasonable likelihood of identifying
a novel gene responsible for the condition.

EXCLUSION CRITERIA:

- A non-genetic disorder or condition, either congenital or acquired, that explains the
growth abnormality, for example, pituitary injury, chronic thyroiditis, whole body
irradiation, or celiac disease.

- In the opinion of the investigators, there is an established diagnosis of a genetic
disorder or condition that explains the growth abnormality and for which the molecular
genetic etiology has already been identified, for example, SHOX deficiency,
hypochondroplasia, or Noonan syndrome.