ACMG PRACTICE GUIDELINES ACMG practice guideline: Genetic evaluation of short stature Laurie H. Seaver, MD1,2, and Mira Irons, MD3, on behalf of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee Disclaimer: This guideline is designed primarily as an educational resource for health care providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from this guideline. Abstract: Short stature is a common indication for genetic evaluation. tinal disease, endocrinopathies, and genetic disorders. These The differential diagnosis is broad and includes both pathologic causes categories are not mutually exclusive, and the molecular basis of short stature and nonpathologic causes. The purpose of genetic of many causes of short stature has already been, and continues evaluation for short stature is to provide accurate diagnosis for medical to be, elucidated. Depending on the availability of the various management and to provide prognosis and recurrence risk counseling subspecialists in the geographic area and the presence or ab- for the patient and family. There is no evidence-based data to guide the sence of associated physical or developmental concerns, the geneticist in an efficient, cost-effective approach to the evaluation of a medical geneticist may be one of the first to evaluate an indi- patient with short stature. This guideline provides a rubric for the vidual with a primary indication of short stature or may be evaluation of short stature evaluation and summarizes common diag- asked to provide consultation regarding genetic testing once a noses and clinical testing available. Genet Med 2009:11(6):465–470. diagnosis is made by other physicians. If the medical geneticist is the primary consultant in the evaluation of an individual with Key Words: short stature, skeletal dysplasia, intrauterine growth re- short stature, then he or she must be familiar with the common striction nonpathologic conditions associated with short stature in addi- tion to the teratogenic and genetic causes. One study reported OBJECTIVE 353 patients referred for genetic evaluation with the primary Ͻ To provide guidance for medical geneticists and other phy- indication of short stature (defined as height 3rd centile). sicians regarding genetic evaluation of pathologic short stature. Almost 50% of the patients were considered to have either constitutional delay of growth or familial short stature. The most common pathologic diagnosis was chromosome abnor- BACKGROUND INFORMATION mality (19%), primarily Turner syndrome, and its variants. In Short stature is a common reason for referral for pediatric 3% of cases, a diagnosis of a recognized multiple malformation subspecialty evaluation. The purpose of genetic evaluation of syndrome was made, and in almost 2% a previously unrecog- short stature is to provide an accurate diagnosis and to provide nized endocrine cause was identified.1 information to the patient and family regarding natural history, The majority of information and guidelines for evaluation of prognosis, available treatment, genetic basis, and recurrence risk. individuals, usually children, with short stature comes from the Potential diagnoses include familial short stature, constitu- pediatric endocrinology literature, particularly addressing eval- tional delay of growth, occult pulmonary, renal or gastrointes- uation for growth hormone deficiency and indications for growth hormone therapy. Although there are a multitude of publications regarding identification of genes associated with From the 1Kapi‘olani Medical Specialists, 2Department of Pediatrics, John A. Burns School of Medicine, Honolulu, Hawaii; and 3Division of Genetics, growth and gene defects associated with short stature, there is a Department of Pediatrics, Children’s Hospital Boston, Harvard Medical paucity of information directed toward the medical geneticist’s School, Boston, Massachusetts. approach to short stature and appropriate genetic testing. The Laurie H. Seaver, MD, Hawaii Community Genetics, 1441 Kapiolani Blvd., most recent publication that specifically addressed the diagnos- Suite 1800, Honolulu, HI 96813. E-mail: [email protected] tic approach to genetic causes of short stature was issued more Disclosure: The authors declare no conflict of interest. than 20 years ago.2 More recently, Kant et al.3 suggested an Submitted for publication March 18, 2009. algorithm for the molecular diagnosis of short stature, although syndromes that may present with only minor anomalies were Accepted for publication March 18, 2009. not included. There is currently no evidence-based literature to Published online ahead of print May 14, 2009. support the diagnostic evaluation of short stature by the medical DOI: 10.1097/GIM.0b013e3181a7e8f8 geneticist. Genetics IN Medicine • Volume 11, Number 6, June 2009 465 Seaver and Irons Genetics IN Medicine • Volume 11, Number 6, June 2009 This guideline will assume that nonpathologic familial short potential.4 Genetic potential or target height is estimated for stature, constitutional delay of growth, hypothyroidism, and boys by calculating the (father’s height [cm]) ϩ (mother’s occult disease have been ruled out as a cause for short stature. height [cm] ϩ 13)/2 and for girls (father’s height [cm]) ϩ This guideline is also meant to apply to patients who might (mother’s height [cm] Ϫ 13)/2. Most children will reach an present for genetic evaluation with the chief concern of short adult height within 10 cm of the target height. The centile for stature, although minor anomalies and some major anomalies this target height at age 18 years can be helpful to determine if may be identified. It is not intended to include all genetic the child is likely, at his or her present height and age, to reach conditions for which short stature may be a feature. Selected that potential. inborn errors of metabolism are included if they are associated Analysis of other growth parameters, including weight and with other physical features or skeletal changes. A brief review head circumference, are also important in the overall analysis of of nonpathologic causes of short stature is included. A diagnos- a child’s growth pattern. In many pathologic types of short tic algorithm is presented along with information regarding stature, weight is affected first, then height velocity, and finally availability and utility of molecular testing for specific genes brain growth (documented by head circumference). Low weight associated with short stature and intrauterine growth restriction for height is more likely due to nutritional deficiency, chronic or (IUGR). occult disease, or other pathologic conditions. Children with endocrine disorders often have short stature with normal weight ANALYSIS OF GROWTH AND PERTINENT for height, or even relative obesity.4 Bone age, as a measure of HISTORICAL INFORMATION skeletal maturity, can also be useful, although a delayed bone age (Ͻ2 standard deviations compared to the chronologic age) The first assessment that must be made when a child presents is nonspecific and associated with many different causes of with short stature is whether a pathologic diagnosis is likely to short stature. Finally, analysis of body proportions, such as arm be present. There are several factors that one must consider in span-to-height ratio and upper to lower segment ratio are also the evaluation of short stature, including genetic potential for helpful in documenting disproportionate short stature. growth, rate of growth, and pattern of growth. The definition Another key component of the evaluation is the time of onset most commonly used for short stature is height-for-age less than of short stature. The small for gestational age (SGA) infant two standard deviations below average for gender, which is presents a special challenge for the medical geneticist. In this demonstrated on the standard growth curves as a length or case, detailed information regarding familial birth measure- height less than the 3rd centile. Standard growth curves used in ments and growth pattern, maternal stature, parity, presence of the United States are based on a North American population; more than one fetus, potential teratogenic exposures, onset of these curves may not apply to all racial and ethnic groups, for growth deficiency, placental function, amniotic fluid volume, which specific growth curves may or may not be available. and the presence or absence of structural anomalies are crucial The single most common useful indicator, in addition to the to the assessment and evaluation. Restriction in fetal growth in absolute height, is growth velocity. Growth velocity is ideally the later stages of pregnancy is suggestive of placental insuffi- assessed by reviewing previous growth points or by remeasure- ciency. Maternal health and surgical history are important to ment over a 4–6 month interval. Crossing of several centile determine potential contribution to