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Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022
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Image from Wikimedia Commons | Judgefloro.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
The image in the slide is of a woman with achondroplasia, the predominant type of skeletal dysplasia.
Growth is a measure of overall well-being and status of chronic disease, as well as any interpersonal and psychological stressors faced by a child.[1] Commonly, the term growth is used synonymously with skeletal growth, which is a determinant of final adult height and is a complex process susceptible to various genetic and physiologic disturbances.[2] Disorders of growth are characterized by aberrant values for a specific age and sex in one or all of the following anthropometric measurements: height, weight, body proportions, osseous maturation, and development of sexual features. Included in these are conditions causing either acceleration or retardation of growth.[3]
Table courtesy of Dr. Qurrat-ul-Ann Saqib; adapted from Wit JM, Ranke MB, Kelnar CJH. EPSE Classification of Paediatric Endocrine Diagnoses. Basel, Switzerland: S Karger AG: 2007.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
The table in the slide lists causes of short stature according to the European Society for Paediatric Endocrinology (ESPE) classification.[4]
Assessment of growth is a key component of preventive child health care. The mainstays of monitoring growth or diagnosing growth disorders in children are a detailed history, a complete physical examination, and appropriate anthropometric measurements (including the child’s height, weight, head circumference, body mass index [BMI], body proportions, and features indicative of sexual maturation).[5]
Diagnostic workup for growth disorders depends on the underlying clinical condition. A basic set of laboratory tests routinely performed includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), urinalysis, antitissue transglutaminase antibodies, thyroid function tests, and karyotyping for Turner syndrome in females with unexplained short stature. A very important imaging study for assessing bone age is an anteroposterior (AP) radiograph of the left hand and wrist.
Management of growth disorders focuses on the underlying etiology and requires a multidisciplinary approach, with the involvement of a general pediatrician, an endocrinologist, a geneticist, a nutritionist, a child psychologist, and other appropriate specialists.
Image from Wikimedia Commons | Mileny ES Colovati, Luciana RJ da Silva, Sylvia S Takeno, Tatiane I Mancini, Ana R N Dutra, Roberta S Guilherme, Cláudia B de Mello, Maria I Melaragno, Ana B A Perez.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Case 1
A 15-year-old girl presents with a progressive history of dyspnea and orthopnea with productive cough for the past 3 months. She had surgery at age 7 years for retinal detachment in the left eye; the surgery was unsuccessful and resulted in left-eye blindness. On examination, she appears tall and thin, with long, bony fingers. Her height is above the 95th centile, with an upper segment–to–lower segment ratio (US/LS) of 0.79. Examination of the cardiovascular system shows findings of mitral regurgitation with congestive heart failure. Echocardiography shows evidence of mitral valve prolapse with moderate mitral regurgitation. On the basis of these findings, a diagnosis of Marfan syndrome is made.
Which of the following is the spine abnormality most commonly encountered in patients with Marfan syndrome?
Bamboo spine
Scoliosis
Disk prolapse
Spinal stenosis
Images courtesy of Malik Muhammad Adil, MBBS.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Answer: B. Scoliosis.
The images above, from a patient with Marfan syndrome, demonstrate scoliosis of the spine.
Marfan syndrome is a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission. Various organ systems are affected by this condition, with skeletal, cardiovascular, and ocular system pathologies predominating. Aortic dissection, aneurysm, and rupture are its most lethal manifestations; Marfan syndrome therefore requires lifelong monitoring with echocardiography or other imaging studies. Overgrowth of the long bones (ie, dolichostenomelia) is often the most striking clinical feature of Marfan syndrome, resulting in a decreased US/LS ratio and an arm span that is long in comparison with height. Establishing a diagnosis of Marfan syndrome is a challenging task and is based on a defined set of clinical criteria—namely, the revised Ghent nosology for Marfan syndrome. Management mainly focuses on preventing complications and genetic counseling and requires a multidisciplinary approach.[1,6]
Image from Rohilla S, Kaushik A, Vinod VC, et al. EXCLI J. 2012;11:538–542. PMID: 27298609. PMCID: PMC4897656.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Case 2
The radiograph in the slide demonstrates the condition known as trident hand.
A 24-month-old girl is brought to the pediatric outpatient department because of her mother’s concern about the child’s inability to walk without support. The patient is the only child from a nonconsanguineous marriage. On examination, she has an obviously large head with a wide-open anterior fontanelle and midfacial hypoplasia. Her head circumference is above the 97th centile, and her length is below the third centile. Examination of her limbs shows a rhizomelic (proximal-segment) type of shortening, bowing of the legs, and trident hands. Motor system examination reveals mild hypotonia. A skeletal survey is ordered; it shows an enlarged calvaria with a small base and narrowed interpediculate distance between lumbar vertebrae.
Which of the following is the most likely diagnosis?
Hypophosphatemic rickets
Diastrophic dysplasia
Achondrogenesis
Achondroplasia
Image courtesy of Malik Muhammad Adil, MBBS.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Answer: D. Achondroplasia.
The radiograph in the slide demonstrates genu varum, as found in achondroplasia, with rhizomelic (proximal-segment) shortening of the bilateral femurs and metaphyseal flaring.
Achondroplasia is the predominant type of skeletal dysplasia, affecting mainly the skull, spine, and extremities and leading to a short-limb dwarfism. It is a nonlethal chondrodysplasia and is inherited as an autosomal dominant trait, though most cases arise from a new mutation in babies born to normal parents. Characteristic phenotypic features include disproportionate short stature, large head, frontal bossing, midface hypoplasia, rhizomelic shortening of the limbs, prominent lumbar lordosis, genu varum, and a trident hand configuration. Infants usually display delayed motor milestones. Intelligence is normal unless central nervous system (CNS) complications such as hydrocephalus develop.[7] Diagnosis is confirmed with the help of skeletal radiographs. Prominent radiographic findings are large skull bones with a small cranial base and narrowing of the interpediculate distance of the lumbar spine. Antenatal testing is available and is usually employed for the diagnosis of homozygous achondroplasia in cases where both parents have achondroplasia.[1]
Image from Wikimedia Commons | Alaska Jack.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Case 3
A 6-year-old girl is brought to a pediatric clinic with a complaint of failure to thrive. She is the product of a nonconsanguineous marriage and was delivered by elective lower-segment cesarean section at 35 weeks’ gestation because of severe intrauterine growth restriction; her birth weight was 1.6 kg. Postnatally, she was admitted to the neonatal intensive care unit (NICU) and was tube-fed initially because of feeding difficulties. Her gross motor milestones were mildly delayed. On examination, she has triangular facies (shown), with a large forehead and clinodactyly of the fifth finger. Her weight and height are both below the third centile, with the occipitofrontal circumference at the 25th centile. Asymmetry of the lower limbs is noted, with hypertrophy of the left lower limb and a leg-length discrepancy of 1 cm.
Which of the following is the most likely diagnosis in this case?
Bloom syndrome
Silver-Russell syndrome
Dubowitz syndrome
Fetal alcohol syndrome
Image from Wikimedia Commons.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Answer: B. Silver-Russell syndrome.
Silver-Russell syndrome is a clinically and genetically heterogeneous disorder associated with intrauterine and postnatal growth retardation.[8] The majority of the cases occur sporadically, but in rare instances, the syndrome may run in families, with an autosomal dominant or autosomal recessive pattern of inheritance. The genetic defect identified in most Silver-Russell syndrome patients is hypomethylation in the chromosome 11p15 imprinting center 1. Characteristic features of this disorder include moderate-to-severe growth failure, with preservation of occipitofrontal circumference, asymmetry (mostly of the limbs), hemihypertrophy, clinodactyly of the fifth finger (shown), developmental delay, and feeding difficulties during infancy. The classic facial phenotype is a child with normal head circumference, blue sclerae, small triangular facies, a high forehead, micrognathia, prominent nasal bridge, and downturning corners of the mouth. Diagnosis is determined mainly on clinical grounds. Management involves optimizing caloric intake for catch-up growth and treatment of feeding difficulties or gastroesophageal reflux, when present. Growth hormone therapy is indicated only in patients who fail to show catch-up growth with adequate caloric intake by 2 years of age.
Image from Medscape.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Case 4
A 15-year-old girl is brought to the outpatient clinic by her mother with a complaint of primary amenorrhea. The mother is also concerned about her daughter’s height and says that the girl is the shortest student in her class. On examination, the teen’s height is found to be at the third centile and her weight at the 75th centile. General physical examination reveals a webbed neck, a low hairline (shown), a shield-shaped chest, and cubitus valgus. Her pubic hair is at Tanner stage 2, and her breasts are prepubertal. Laboratory investigations show markedly elevated gonadotropin levels (FSH > LH), with a low serum estradiol. On the basis of these findings, a working diagnosis of Turner syndrome is made; this is confirmed with karyotyping.
Which of the following tests is not part of the workup performed in diagnosing Turner syndrome?
Thyroid function tests
Ultrasonography (US) of the abdomen and pelvis
Growth hormone provocation test
Echocardiography
Image from Medscape.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Answer: C. Growth hormone provocation test.
Turner syndrome is the most common sex chromosome anomaly in females, with a frequency of approximately 1 in 2000 female live births.[9] It occurs when some portion of a short arm of one X chromosome is deleted or one X chromosome is completely absent, leading to a 45XO karyotype. Some cardinal clinical features of Turner syndrome are lymphedema of the hands and feet (shown), webbed neck, shield chest, cubitus valgus, hyperconvex fingernails, short fourth or fifth metacarpal, and short stature. The syndrome is also associated with a constellation of potential abnormalities involving multiple organ systems (eg, reproductive, cardiovascular, renal, gastrointestinal, otolaryngologic, skeletal, and endocrine). Short stature and ovarian failure leading to primary or secondary amenorrhea are the most common presenting complaints. Workup includes karyotyping, echocardiography, gonadotropin-level analysis, and renal and pelvic US. Patients with Turner syndrome should be routinely screened for hypothyroidism, diabetes mellitus, celiac disease, scoliosis, hypertension, and sensorineural hearing loss. Treatment involves a multidisciplinary approach to screening for and management of chronic diseases, growth hormone therapy in childhood, and hormone replacement with estrogens starting around 12-14 years of age, along with psychosocial support.
Image from Wikimedia Commons | ADSLLC.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Case 5
A 14-year-old boy comes to the pediatric clinic, accompanied by his mother, with a complaint of being shorter than his peers. He is also concerned that other boys in his class are more “manly-appearing” than he is. According to his mother, he has always been shorter than his cousins and friends, but the difference is more noticeable now. His mother’s age of menarche was 14.5 years, and his father started shaving at 15 years. You plot the boy’s height and weight on the growth chart and calculate midparental height and growth velocity (6 cm). His pubic hair is at Tanner stage 1, and his testicular volume is 3 mL. The rest of the examination is normal. You order a skeletal bone-age radiograph.
In considering a diagnosis of constitutional growth delay, which of the following would be expected?
Height age = bone age, with both < chronologic age
Chronologic age = bone age, with both > height age
Height age = bone age = chronologic age
Height age > bone age, with both < chronologic age
Image from Clarke SL, Bowron A, Gonzalez IL, et al. Orphanet J Rare Dis. 2013 Feb 12;8:23. PMID: 23398819. PMCID: PMC3583704.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Answer: A. Height age = bone age, with both < chronologic age.
The radiograph in the slide, from a male with severe constitutional growth delay, shows a bone age that is much lower than the chronologic age.
Constitutional growth delay is the most common cause of short stature and pubertal delay in children.[10] It is a variant of normal growth and is characterized by slowing of weight and height gain as early as infancy, with a downward crossing of centile lines until the age of 2-3 years. From then until puberty, growth velocity is normal. The onset of puberty and pubertal growth spurt is also delayed, but the final adult height is normal compared with that in persons with familial short stature, another variant of normal growth, in which the child’s ultimate height is short (corresponding to his or her genetic potential).[11] The history in constitutional growth delay may reveal that one or both of the child’s parents had delayed puberty and pubertal growth spurt. Physical examination is essentially normal, and workup includes a CBC with differential, routine blood chemistries, ESR, and urinalysis to rule out any underlying chronic illness. Radiography of the left hand and wrist is performed to determine bone age, which is delayed and corresponds to the height age. Management focuses on regular follow-up for plotting growth velocity and reassurance of the child, as well as the parents, as to the benign nature of this condition. In adolescents experiencing psychosocial stress because of their condition, a short course of sex hormones may be given.
Image courtesy of Dr Qurrat-ul-Ann Saqib.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Case 6
A 5-year-old girl comes in with a history of failure to thrive since birth. Her mother is very worried, given that the patient’s sister, who is 2 years younger, is now taller than she is. The history is significant for episodes of afebrile fits in the neonatal period, which resulted from low blood glucose levels, as well as delayed dentition. There are no features suggestive of any chronic illness. On examination, the patient has “cherubic facies,” with a height under 3 SD below the mean and a weight under 1.5 SD below the mean. The rest of the physical examination yields normal results. According to the patient’s previous record, her growth velocity was 3 cm in the past year. A radiograph of the left wrist and hand reveals a bone age of 2 years. Values from serum chemistries, urinalysis, and thyroid function tests are within normal limits. On the basis of these findings, a provisional diagnosis of isolated growth hormone deficiency is made.
Which of the following would be the next investigation of choice in this child?
Genetic testing for mutations causing growth hormone deficiency
Insulinlike growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) levels
Cranial magnetic resonance imaging (MRI)
Serial serum growth hormone levels
Image from Wikimedia Commons | Nevit Dilmen.
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Answer: B. Insulinlike growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) levels.
The molecular structure of IGF-1 is shown above.
Growth hormone deficiency can result from disruption of the normal growth hormone axis in the higher brain, hypothalamus, or pituitary. This dysfunction can be either congenital or acquired. The deficiency may be isolated or may be associated with other pituitary hormone deficiencies. Most cases of isolated growth hormone deficiency, as in our patient, are idiopathic. The clinical presentation of children with isolated growth hormone deficiency is failure to thrive, which is especially manifested as extreme short stature. The birth height and weight parameters are usually normal, but the patient may experience episodes of hypoglycemia in the neonatal period. In infancy and at toddler age, these patients typically cross the centile lines downward on the growth chart and have cherubic facies, mild truncal obesity, and delayed dentition. When plotted on the growth charts, their height velocity is slower than normal, and they do not fall within the target height range calculated according to the midparental height.[12] Workup involves laboratory investigations to rule out common causes of growth failure and other pituitary hormone deficiencies, radiographic assessment of bone age, IGF-1 and IGFBP-3 levels, growth hormone provocation tests, cranial MRI to exclude pituitary abnormalities, and genetic testing. The mainstay of management in cases of isolated growth hormone deficiency is daily administration of subcutaneous injections of recombinant human growth hormone. Response to therapy is monitored by regular height measurements and bone-age assessment when indicated.
courtesy of Dr Qurrat-ul-Ann Saqib
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Case 7
A 3.5-year-old boy is admitted to the pediatric ward with complaints of short stature and abdominal distention for the past year. He is the product of a nonconsanguineous marriage and has two older sisters who are alive and healthy. His birth history is normal, and his developmental age is 2 years. One of the boy’s maternal uncles died at the age of 13 years, and according to the mother, the boy’s facial features resemble those of his uncle. On examination, his height and weight are both below the third centile, with a US/LS of 1:1 (normal for this age is 1.3:1). The patient also has coarse facial features, thick skin, joint stiffness, and a protuberant abdomen with firm hepatosplenomegaly. There is no corneal clouding. Hearing assessment reveals conductive deafness. On the basis of these findings, a diagnosis of mucopolysaccharidosis (MPS) is made, and a skeletal survey is ordered to look for dysostosis multiplex.
On the basis of the clinical findings, which of the following types of MPS is most likely in this patient?
Hurler syndrome
Hunter syndrome
Sanfilippo syndrome
Morquio syndrome
from Medscape
Growth Disorders: 7 Cases of a Developing Problem
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics; Sumaira Nabi, MBBS, FCPS Neurology | July 27, 2022 | Contributor Information
Answer: B. Hunter syndrome.
MPS is a collective term for a group of chronic progressive storage disorders in which deficient activity of lysosomal enzymes leads to accumulation of partially degraded glycosaminoglycans (GAGs) in the lysosomes and extracellular tissues. MPS is classified into seven different phenotypes on the basis of clinical features. All of these are inherited in an autosomal recessive fashion except for Hunter syndrome (MPS II), which is inherited in an X-linked recessive fashion. These patients initially have normal development, with the onset of symptoms occurring in infancy or childhood. Various organ systems may be involved, including the CNS, the cardiovascular system, the respiratory tract, and the musculoskeletal system, along with ophthalmologic disease and hearing impairment. Phenotypic features common to all subtypes include coarse facial features, growth failure, and organomegaly. Diagnostic studies include urinalysis for excretion of GAG fragments and enzymatic assay for the deficient enzyme in serum, leukocytes, or cultured cells. A constellation of skeletal abnormalities known as dysostosis multiplex (shown) is seen on plain radiographs. Management includes a multidisciplinary approach for periodic assessment of organ system involvement, along with supportive care and enzyme replacement if feasible. No completely curative treatment is available, but bone marrow transplant can lead to significant clinical improvement. In untreated children, the cause of death is usually cardiorespiratory compromise in the first decade of life.[13]
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Authors
Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics
Consultant Pediatrician
Department of Pediatrics
Kulsum International Hospital
Islamabad, Pakistan
Disclosure: Qurrat-ul-Ann Saqib, MBBS, FCPS Pediatrics, has disclosed no relevant financial relationships.
Sumaira Nabi, MBBS, FCPS Neurology
Assistant Professor and Consultant Neurologist
Department of Neurology
Pakistan Institute of Medical Sciences
Islamabad, Pakistan
Disclosure: Sumaira Nabi, MBBS, FCPS Neurology, has disclosed no relevant financial relationships.
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References
Bamba V et al. Assessment of growth. Kliegman RM et al, eds. Nelson Textbook of Pediatrics. 21st ed. Philadephia: Elsevier; 2020: Chap 27.
Haymond M et al. Early recognition of growth abnormalities permitting early intervention. Acta Paediatr. 2013 Aug;102(8):787-96. PMID: 23586744 [Full text].
Wit JM et al. EPSE Classification of Paediatric Endocrine Diagnoses. Basel, Switzerland: S Karger AG; 2007.
Graber E et al. Growth and growth disorders in children and adolescents. Pediatr Ann. 2012 Apr;41(4):e1-9. PMID: 22494211
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