Nedim Cakan, MD

A 14-year-old white girl whose menstrual periods have not begun presents with concerns that many of her peers are already menstruating.

 The patient weighs 50 kg (110 lb, 50th percentile) and is 58.5 in tall (third percentile). She was 49 in at age 10 and 54 in at age 12. Her father is 5 ft 7.5 in tall (25th percentile) and her mother is 5 ft 2.5 in tall (25th percentile). 

The patient's blood pressure is 100/60 mm Hg. She is in Tanner stage 2 for breast and pubic hair development and has normal female external genitalia. Physical findings and past medical history are unremarkable.

 The patient has a normal hemogram, normal thyroid function, and normal bone age. Levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are slightly elevated; estradiol levels are low. 

Definitive diagnosis is made by chromosome analysis. Karyotyping shows 46,XX/45,X.

A 7-year-old African American girl sees her pediatrician because she is considerably shorter than her peers. She was born at 41 weeks' gestation after an uncomplicated pregnancy and had a normal postnatal course. She weighed 3.42 kg (7.5 lb)at birth (50th percentile) and was 18.7 in long (30th percentile). Her past medical and family histories are unremarkable.

 She now weighs 24 kg (53 lb, 60th percentile) and is 42 in tall (below the fifth percentile). She previously measured 36 in at 4 years and 39 in at 6 years. Her father is 6 ft tall (75th to 90th percentile), her mother is 5 ft 5 in tall (50th to 75th percentile), and her 5-year-old sister is 41 in tall (50th to 75th percentile). Midparental height is 66 in (calculated by adding the mother's height to the father's height and dividing by 2, then subtracting 2.5 in for girls). 

Aside from short stature, physical examination findings are normal. The patient is in Tanner stage 1, with normal female external genitalia. She also has a normal hemogram, normal thyroid function, and normal bone age. Karyotyping shows 45,XO. 

Growth charts for the patients in both cases are shown here (

Figure 1 - The patient in case 1 is in the third percentile for height, and the patient in case 2 is below the fifth percentile for height. Nearly 100% of patients with Turner syndrome are of short stature.

WHAT IS THE DIAGNOSIS-AND WHAT ARE THE TREATMENT OPTIONS?

Both patients presented with short stature; the first also had primary amenorrhea. In both cases, physical findings were unremarkable except for short stature. Thus, a normal physical examination does not rule out Turner syndrome (TS). 

Although in recent years TS is often recognized in utero, many patients with mosaicism do not have the "classic" features of this disorder- and the diagnosis might therefore be easily missed until pubertal years when the patient is amenorrheic (as with the patient in case 1). Therefore, chromosomal analysis should be considered for girls of any age who have unexplained short stature (

). Early diagnosis is crucial for appropriate treatment and counseling.

Figure 2 - Chromosomal analysis should be considered for girls of any age who haveunexplained short stature. Patients with Turner syndrome lack part or all of an X chromosome,as can be seen here.

 Patients with TS lack part or all of an X chromosome. The most common sex chromosome abnormality in females, TS occurs in approximately 50 per 100,000 liveborn girls.

 Roughly 10% of spontaneously aborted fetuses have this disorder, and the incidence has been estimated to be 0.8% in zygotes. As such, it may be the most common chromosomal disorder in humans.

 It appears that only about 1% of human 45,X zygotes survive to term, and those who do typically have a characteristic set of somatic abnormalities.

 TS can develop from the following mechanisms:

     X chromosome monosomy, which is associated with a     loss of the whole X chromosome.

     X chromosome mosaicism, in which a sex chromosome     may also be lost during early stages of embryonic     development, such that only some cells receive a single     X chromosome.

     X chromosome defects, such as fragmented or deleted     portions and ring formation. 

Short stature homeobox (SHOX) is a transcription factor that plays a particularly important role in the growth and maturation of bones in the arms and legs. One copy of the SHOX gene is located on each of the sex chromosomes (the X and Y chromosomes) in the pseudoautosomal region.

 Females with TS have only 1 copy of the SHOX gene instead of the usual 2 copies; this reduces the amount of SHOX protein by half. Researchers believe that this deficiency is at least partly responsible for short stature and skeletal abnormalities (such as unusual rotation of the wrist and elbow joints) in females with this condition.

The common clinical presentations of TS are short stature, lymphedema of the hands and feet (

), a broad chest with widely spaced nipples, a low hairline, low-set ears, cubitus valgus, webbed neck (

), and amenorrhea. The Table describes the myriad manifestations. 

Figure 3 - Lymphedema of the feet is commonly seen in girls with Turner syndrome.

Figure 4 - The widely separated nipples and webbed neck of this newborn are common manifestations of Turner syndrome.

 Patients with TS generally have normal intelligence. The exception is the rare patient with a tiny X-ring chromosome, who may present with severe mental retardation. TS patients may have problems with visuospatial organization (eg, difficulty in driving), deficits in social cognition, trouble with nonverbal problem-solving tasks (eg, math problems), psychomotor deficits (such as clumsiness), and attention-deficit disorder.

The neurodevelopmental abnormality may result from the X-chromosome monosomy or from hormonal deficiencies associated with gonadal dysgenesis.

 It is compatible with right cerebral dysfunction, and the deficits generally involve nonverbal skills. 

 Multispecialty team management is crucial for girls with TS. The primary care pediatrician orchestrates the team.

 GH is being used successfully to treat girls with short stature. The earlier the GH therapy is initiated and the higher the dosage, the more robust the response is.

 The goal of the therapy is to attain a normal height for age as soon as possible; growth should progress through puberty so that the patient attains a normal adult height.

 Although GH can increase the patient's adult height, many factors influence this, including

     The patient's height and age at initiation of therapy.

     Concurrent treatment with anabolic steroids. 

The timing of estrogen replacement therapy.

 For a young girl of normal height, GH therapy should be initiated at the FDA-approved dosage of 0.054 mg/kg/d. Levels of insulin-like growth factor (IGF-1) should be kept below 2 SD above the mean. For an older girl who is short, consider giving 0.067 mg/kg/d and increasing the dosage to 0.1 mg/kg/d to provide catch-up growth, regardless of the IGF-1 level.

 Oxandrolone is the preferred androgen because it cannot be aromatized. It is also unlikely to produce virilizing effects or advancement in bone age at low dosage. When used alone, anabolic steroids increase short-term growth velocity but do not appear to improve the final height. Oxandrolone, in combination with GH, augments growth.

 Estrogens are important in the development of secondary sex characteristics and maintenance of the female reproductive system.

 They also cause growth and development of the uterus, fallopian tubes, and vagina. Along with other hormones, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat.

 The timing of estrogen therapy is important. The longer the duration of estrogen-free GH treatment, the greater the final height attained. In one study, growth was stimulated for approximately 2 years after the initiation of estrogen therapy but then declined as bone age advanced.

 It was found that girls whose estrogen therapy was delayed until 15 years of age gained more height.

All patients with TS should have a baseline cardiovascular evaluation at the time of diagnosis. Females with a normal echocardiogram should undergo imaging every 5 years to rule out aortic root dilation. Those with abnormal echocardiographic findings need to be followed more frequently by the cardiologist. Aortic dissection must be considered in any TS patient with severe chest pain, and MRI scans should be obtained urgently.

Routine screening with ultrasonography for renal abnormalities is also indicated for patients with TS.

 If results are abnormal, refer the patient for evaluation and therapy. Urinary tract infections should be treated vigorously and renal obstruction (if any) must be promptly relieved. 

Psychological assessment should also be part of the treatment plan for each child with TS. Evaluation of intellectual, learning, and motor skills as well as social maturity is recommended before the child is enrolled in preschool programs. If cognitive strengths and weaknesses are identified, preventive and intervention strategies can be helpful. The adjuvant role of pubertal estrogen replacement on cognitive function remains unclear.

 Many couples choose to adopt. Ovarian tissue and preservation of oocytes might be a possibility for future fertility treatments in patients with TS. The pregnancy rate achieved by embryo transfer in women with TS is similar to that of other oocyte recipients with primary ovarian failure. 

Articles

Two Girls With Short Stature

A 6-month-old white girl presented with a 2-day history of fever and respiratory symptoms. Initially, she was admitted with a diagnosis of respiratory syncytial virus bronchiolitis. In addition to her respiratory findings, widespread signs of rickets were found--ie, frontal bossing, rachitic rosary, widening of the wrists, and double maleoli.

The child had been born to a 19-year-old gravida 2, para 2 mother via cesarean birth secondary to malpresentation and fetal distress. The child weighed 3.06 kg at birth. She currently weighed 6 kg (5th percentile); she was 62 cm tall (5th to 25th percentile); head circumference, 46 cm (95th percentile or higher). Laboratory findings: calcium, 9.7 mg/dL; phosphorus, 2.8 mg/dL, immunoreactive parathyroid hormone, 95 pg/mL (normal, 7 to 53 pg/mL); alkaline phosphatase, 521 U/L (normal, 50 to 330 U/L); and urinary phosphorus, 870.4 mg/dL.

X-ray films revealed florid signs of rickets, including a rachitic rosary and cupping of ribs, and fraying and flaying of the radius, ulna, femur, tibia, and fibula (

A dietary history revealed that the child had been fed a soy-based formula since early infancy because she had been unable to tolerate cow's milk. She drinks approximately 5 oz of soy-based formula every 2 to 3 hours and recently started to eat baby food.

A diagnosis of hypophosphatemic rickets was made. Therapy with vitamin D (calcitriol) and phosphorus supplementation was initiated.

The child's mother had rickets as a child, which left severe deformities. She was taking vitamin D and phosphorus supplements. The patient's 18-month-old sister had a history of delayed gross motor milestones and also had frontal bossing; however, a workup had never been done, nor had the child been treated.

Familial hypophosphatemic rickets is the most common nonnutritional form of rickets. The term "vitamin D-resistant rickets" was originally used to describe rickets that was refractory to treatment with vitamin D. It was later found that renal phosphate wasting and a low serum phosphate concentration were common factors in many refractory cases. This discovery led to the name "phosphate diabetes." This disorder now is more appropriately named "hereditary hypophosphatemic rickets." The usual mode of inheritance is X-linked dominant.

X-linked hypophosphatemic (XLH) rickets is the most common form of rickets in developed countries.

 Other forms of hypophosphatemic rickets include autosomal dominant,

 autosomal recessive hereditary hypophosphatemic rickets with hypercalciuria,

 and oncogenic tumor-induced osteomalacia.

The pathogenesis in XLH rickets involves a defect in proximal tubular reabsorption of phosphate and the conversion of 25-dihydroxy (OH) vitamin D to 1,25-dihydroxycholecalciferol (1,25[OH]

 Studies indicate reduced activity of sodium-dependent phosphate transporter in the renal tubule.

Great strides have been made with the discovery of the gene responsible for XLH rickets on chromosome Xp22.1. This gene was named "PHEX" (

chromosome). Mutations in the PHEX gene result in under-expression of the sodium-phosphate co-transporter that is responsible for phosphate reabsorption in the proximal tubule.

 The PHEX gene inactivates hormone-like substances (called phosphatonins) that promote phosphate excretion and impair bone mineralization.

 In patients with XLH disease, these phosphatonins are not activated; consequently, they circulate in high concentrations, which leads to excessive phosphate excretion. Hormones recognized to be phosphatonins are fibroblast growth factor 23 (FGF23), matrix extracellular phosphoglycoprotein

In autosomal dominant hypophosphatemic rickets, the FGF23 gene mutations on 12p13 interfere with its cleavage.

 Overproduction of FGF23 may be responsible for tumor-induced osteomalacia.

XLH rickets usually presents when a child begins to bear weight (ie, during the second or third year of life) and is manifested by the child's reluctance to walk. In XLH disease, the degree of involvement is less severe in heterozygous females. Nevertheless, no gender differences in disease severity were detected in the largest reported series of patients with XLH rickets.

 Affected patients grow slowly and have delayed dentition, dental abscesses, and early tooth decay. Males are affected more frequently than females.

 Both males and females may also have gross clinical findings of rickets; the lower extremities are more affected than the upper extremities. Enthesopathy (calcification of tendons, ligaments, and joint capsules) is a common finding.

Hypophosphatemia and normal to slightly low calcium, normal to high parathyroid hormone, and increased alkaline phosphatase levels is a typical laboratory profile in patients with XLH rickets. The calcitriol level is normal or slightly low (inappropriately, because hypophosphatemia stimulates vitamin D synthesis). Urinary loss of phosphate is always above reference ranges. Tubular reabsorption of phosphorus is 60% or less (normal is between 85% and 100%). Urinary calcium levels help distinguish this from hypercalciuric variants.

In all cases, radiography is the study of choice. However, there is no pathognomonic sign that differentiates hypophosphatemic rickets from any other type of rickets (

). Histologically, osteomalacia and hypomineralized periosteocytic lesions are typically seen.

Autosomal dominant rickets manifests with hypophosphatemia and phosphaturia but minimal or no associated skeletal changes. Studies reveal that children present with phosphate wasting, rickets, and lower extremity deformity; some lose the renal phosphate-wasting defect after puberty. Adolescents and adults present with renal phosphate wasting, bone pain, weakness, and fractures but not with lower extremity deformity.

In patients with autosomal recessive hypophosphatemic rickets, renal tubular phosphate handling is impaired but the response of a-hydroxylase to hypophosphatemia is intact. Thus, calcitriol levels are elevated, which increases intestinal calcium reabsorption and leads to hypercalciuria and osteopenic bones. Tumor-induced osteomalacia also has clinical findings similar to those of autosomal recessive hypophosphatemic rickets.

The goals of therapy are to improve growth, reduce the severity of bone disease, and minimize activity limitations. Phosphate and calcitriol are the mainstays of therapy. Phosphorus lowers the concentration of ionized calcium in plasma. Hypophosphatemia stimulates calcitriol synthesis; administration of phosphorus decreases calcitriol synthesis. There is secondary hyperparathyroidism from hypocalcemia. Increased levels of parathyroid hormone further aggravate phosphorus loss. Calcitriol administration is therefore necessary to increase the intestinal absorption of calcium and phosphorus and to prevent secondary hyperparathyroidism.

Therapy with calcitriol (Rocaltrol, Calcijex) is initiated at 15 to 20 ng/kg/d. The dosage is gradually increased over several months to 30 to 60 ng/kg/d. Phosphate salts are given at 0.5 to 1 g/24 h in a younger child and at 1 to 4 g/24 h in an older child in divided doses every 4 hours at least 5 times a day. Joulie's solution contains 30.4 mg of phosphorus per milliliter. Phospha-soda (Fleet) solution contains 127 mg of elemental phosphorus per milliliter. An older child may use Neutra-Phos-K powder (250 mg of elemental phosphorus per packet or capsule). The phosphorus dosage should be increased in 250- to 500-mg increments to a maximum of 3500 mg/d.

Affected children should be seen every 3 months. Healing typically starts in 6 to 8 weeks after the start of therapy. Monitor height; levels of serum calcium, phosphate, and alkaline phosphatase; and the urinary calcium- to-creatinine ratio (a ratio above 0.25 indicates hypercalciuria and the need to reduce the dose of 1,25[OH]

 Radiographs of the hand should be obtained to determine bone age and to monitor for the reappearance of rickets. Renal ultrasonography should be done to evaluate for nephrocalcinosis--a well-recognized complication of therapy.

Treatment is similar for the autosomal dominant form of rickets and for tumor-induced osteomalacia. The latter type is generally refractory to medical therapy; the defect in vitamin D metabolism is more severe and often results in low 1,25(OH)

D levels. The syndrome is cured when the tumor is removed.

Hypophosphatemic rickets with hypercalciuria responds to phosphorus replacement alone.

 Thiazide diuretics are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis. Amiloride (Midamor) is used to counter hypokalemia as a result of thiazide therapy.

 This has been tried in clinical trials in addition to the usual treatment. However, there are no current recommendations for this therapy.

 Non-hypercalcemic analogs of vitamin D (ie, 24,25[OH]

Despite medical therapy, some patients require surgical correction of severe bow defects. Because of the short half-life of 1,25(OH)

D and 1a-hydroxyvitamin D, it is not necessary to interrupt therapy before surgery. However, it is mandatory to monitor the urinary calcium-to-creatinine ratio. If the ratio exceeds 0.25, discontinue the 1,25(OH)

Hypervitaminosis D occurs secondary to high doses of fat-soluble vitamin D and infrequent monitoring of serum and urine biochemistries.

 This complication is much less common today with the use of 1a- hydroxylated vitamin D metabolites.

Nephrocalcinosis, another complication, has been linked to excessive doses of calcitriol and to noncompliance with oral phosphate supplementation; the condition is associated with renal tubular acidosis.

 Hyperparathyroidism may develop from the stimulatory effect of phosphate on the parathyroid. Concomitant use of calcitriol dampens this effect.

Affected persons have a normal life span. With early diagnosis and good compliance with therapy, deformities can be minimized.

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  Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. 

  Lorenz-Depiereux B, Benet-Pages A, Eckstein G, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. 

  Chesney RW. Familial hypophosphatemia (vitamin D-resistant rickets associated with tumor). In: Behrman RE, Kliegman R, Jenson HB, eds. 

 Philadelphia: Saunders; 2004:2345-2346.
 

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 Philadelphia: Saunders; 2004:2346-2347.
 

 Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization. 

  Hruska KA, Rifas L, Cheng SL, et al. X-linked hypophosphatemic rickets and the murine Hyphomologue. 

  Xiao ZS, Crenshaw M, Guo R, et al. Intrinsic mineralization defect in Hyp mouse osteoblasts. 

  Rowe PS, de Zoysa PA, Dong R, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. 

  Berndt T, Craig TA, Bowe AE, et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. 

  White KE, Carn G, Lorenz-Depiereux B, et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. 

  Shimada T, Mizutani S, Mutu T,et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.

Author | Nedim Cakan, MD

Articles

Two Girls With Short Stature

Case in Point: Hypophosphatemic Rickets