Rickets is caused by vitamin D deficiency that results in osteomalacia, the delayed or inadequate mineralization of osteoid in mature cortical and spongy bone (5). Rickets is a rare condition in the United States. However, it may be found in higher numbers in dark-skinned breastfed babies who are not supplemented and all breastfed babies who themselves and/or their mothers have little to no exposure to the sun on a daily basis. Typically, this becomes problematic after 6 months of age.

CLINICAL CHARACTERISTICS. The clinical features of nutritional rickets include early-onset craniotabes, rachitic rosary (costochondral junction enlargement), and thickening of the wrists and ankles. As rickets continues, clinical findings include progressive bowing of the legs; poor linear growth; and abnormal serum calcium (ionized calcium is the most accurate test), phosphate, and alkaline phosphatase levels. In severe cases, the baby may have seizures.

DIAGNOSTICS. The diagnosis of rickets is made with radiographic demonstration of metaphyseal flaring, cupping, and decreased mineralization of the distal meta-physic, as well as laboratory evidence of elevated alkaline phosphatase.

TREATMENT. The treatment includes supplementation of vitamin D and/or formula. If left untreated, permanent deformities may ensue.


Mucopolysaccharidoses (MPS) are hereditary progressive conditions secondary to mutations in genes that code for enzymes responsible for lysosomal degradation of glycosaminoglycans (GAGs) (formerly called mucopolysaccharides) (382). The underlying problem is a defect in the degradation of GAGs leading to the accumulation of lysosomes (vacuoles found in almost all cells) (383). All seven types of MPS are a form of lysosomal storage disease. The accumulation of GAGs results in clinical sequelae in respiratory, cardiac, gastrointestinal, neurologic, and musculoskeletal systems. For MPS I, II, IVA, and VI there is recombinant human, enzyme replacement therapy (ERT) available (384-390). ERT was first available in 2001 and approved in 2003 for MPS type I (537). Therefore, ERT in MPS is a young and vibrant field of vast research worldwide. Hematopoietic stem cell transplantation (HSCT) has shown improvement in MPS I (382,391), particularly in regard to neurologic deterioration. Gene therapy holds promise and risk (391).

Various parameters to assess walking and endurance such as the 6-minute walk test, have been used in studies at multiple sites nationally and internationally. ERT in the MPS VI population has demonstrated improvement in endurance, ambulation, pulmonary function, and survival (390). Similar benefits from ERT have been shown in MPS I, MPS II, and MPS IVA. ERT has variable clinical outcomes depending on the age that it is initiated and the organ system studied. Following ERT, there is still significant morbidity with regard to cardiac valve, skeletal, and joint disease. Therefore there is rationale to start ERT early before disease sequelae progress. Marked heterogeneity exists within each of the seven groups, and life expectancy for some can be before the first decade and can reach into the fifth decade or even more (382). Many of these individuals appear normal at birth. In general, the later the clinical onset, the slower the clinical picture (383,392).

CLINICAL CHARACTERISTICS. The cranium is typically disproportionately large and the facial features are coarse and may include bushy eyebrows, corneal clouding, prominent forehead, a depressed nasal bridge, thick lips, and enlarged tongue. Short stature is present to some degree in all seven types. Odontoid hypoplasia and resulting atlantoaxial instability along with accumulation of GAGs in the atlantoaxial area compressing the spinal cord frequently require decompression and fusion. This is a major complication of this condition, potentially causing spinal cord compression with resulting respiratory compromise and tetraplegia. The time of surgical intervention is critical. Contractures may present at the shoulders, elbows, forearms with decreased supination, fingers, hips, knees, and ankles. Fingers are short and stubby, and hands are wide. Fingers typically have flexion contractures along the distal interphalangeal (DIP) joints. Carpal tunnel syndrome (CTS) is common. Typically, the presenting complaint for CTS is difficulty with fine motor tasks, not pain (393). Release of the carpal tunnel at our institution has improved the DIP contractures presumably because there is more room for the tendons to glide once released. Cognitive decline is difficult to predict in young patients. Mental deterioration eventually occurs in most type III individuals and those with severe types I, II and VII. Kyphosis can appear early and is usually marked. Blindness may result from optic atrophy or corneal clouding. Deafness may occur as well. Dysostosis multiplex is a constellation of radiological findings: thickened diaphyses, bullet-shaped metacarpals, hypoplastic epiphyses, spatulate ribs, abnormally shaped vertebrae, and enlarged skull (394). Individuals with MPS require regular imaging of the spine and hips, at least until skeletal maturity.

SPECIFIC TYPES. MPS are typically divided into seven groups and subgroups as MPS III A, B, C, and D or MPS IVA and IVB, each with one or more deficient enzymes. In MPS I, there are three clinical subtypes all with mutations in the same gene: the most severe form is Hurler's syndrome and the mildest form is Scheie syndrome (MPS I-S, formerly MPS V). The mode of inheritance is autosomal recessive for all groups except MPS II Hunter's disease, which is X-linked recessive. Type III is Sanfilippo A, B, C, D. Type III is the most difficult to diagnose because it does not have the clinical features prominent in the other types and is primarily a syndrome involving the nervous system. Falling, hyperactivity, attention deficit, or speech and sleep problems may be the first signs of this condition.

Type IVA and IVB Morquio syndrome: Type IVA, the more common of the two types, is characterized by normal intelligence and gross motor milestones early in life. Over time, gait may progressively worsen with severe genu valgum, ligamentous laxity, pes planus, hip dysplasia, and increased sternal protrusion. The chest deformity can be restrictive and cause cardiorespiratory symptoms (392). Many of these individuals do not reach normal body length.

Type VI Maroteaux-Lamy has the facial features typical of MPS; intellect generally remains normal; and obstructive sleep apnea, corneal clouding, and deafness are common. VII Sly type can present as hydrops fetalis, or life expectancy can be into the second decade. There can be a wide variability of cognitive ability. Type IX, Natowicz syndrome, is characterized by normal intelligence, short stature, and painful masses around joints and is extremely rare, with four known individuals with this type of MPS.

REHABILITATION. A multidisciplinary approach is essential for the management of individuals with MPS. Specific rehabilitation issues may include hand and wrist bracing to help avoid progression or formation of contractures of the wrist and fingers and help with the management of CTS. Lower extremity bracing, walkers, and gait trainers can help with ambulation and postural alignment. A TLSO for the back may help prevent progression of scoliosis. Aids for functional independence are essential. Quality of life was increased with decreased dependency of wheelchair use in those with Morquio IVA syndrome (395). Power mobility for community independence is essential for many with MPS.

MEDICAL AND SURGICAL INTERVENTIONS. SEPs can be helpful in determining compression of the cervical spine (396). SEPs can be done at 6- to 12-month intervals to look at changes in latency of the waveforms. Yearly MRIs for monitoring cord compression and potential surgery are typically used in the United States. There is an increased risk with anesthesia, and a medical center with an anesthesia team that specializes in this condition is recommended. Intraoperative monitoring for surgical procedures is important to make sure that the spinal cord is stable and the neck is in good position during anesthesia. The use of an ultrathin fiberoptic bronchoscope may be necessary during intubation.

Carpal tunnel release can lead to improved function and can decrease contractures of the DIPs. Cervical spine decompression and stabilizing is important to prevent tetraplegia and ventilator dependency. Hip surgery is also important for transfers and ambulation. The ERT does not cross the blood-brain barrier or enter the joint space/ cartilage or cornea. There are trials as this chapter goes to press on intrathecal ERT for MPS I and MPS II (Clinical-Trials.GOV). Earlier HSCT in MPS I is thought to have the best possibility of good results. VP shunt can help manage hydrocephalus (392). Genetic consultation is important secondary to prolonged life expectancy with ERT (397,398).


Sickle Cell Anemia

Sickle cell anemia has been discussed earlier in this chapter. The reader is referred to external references for additional discussion as needed.

Chronic Kidney Disease

Children with chronic kidney disease (CKD) are at great risk for short stature. Adequate nutrition may be problematic. With failing kidneys, erythropoietin production is inadequate and anemia may result. These children may be resistant to their own elevated GH and may require recombinant human GH subcutaneously (399). Renal osteodystrophy is a term that describes the bone disorder spectrum in CKD. It is most commonly associated with a high turnover bone disease secondary to hyperparathyroidism (399). Osteitis fibrosa cystica is the pathologic skeletal finding in this condition. In CKD there are calcium and phosphate metabolism changes that lead to hyperparathyroidism, hyperphosphatemia, calcitriol deficiency, and hypocalcemia. The osteocyte produces a circulating peptide called FGF23 that is instrumental in regulating the excretion of phosphate. There is an increase in FGF23 for all age groups with CKD, and this is inversely proportional to the glomerular filtration rate. In addition, there is defective hydroxylation of vitamin D.

Vitamin D supplementation (both inactive and active forms) may reduce cardiovascular morbidity and proteinuria by improving hyperparathyroidism. Additionally, phosphate binders (that do not contain calcium) decrease mortality of adults with CKD and show promise in the treatment of the pediatric population as well (400). The excessive parathyroid hormone is a response to correct the hypocalcemia by increasing the bone resorption (399). Clinically, these patients have muscle weakness, bone pain, and fractures from minor trauma. Rachitic changes as well as varus and valgus deformities of the long bones and SCFEs may be seen in growing children. The x-rays demonstrate subperiosteal resorption and widening of the metaphyses in the hands, wrists, and knees (399). Medical management for this condition is by a nephrologist. Diets include low phosphorus, phosphate binders, vitamin D, and noncalcium-based diets for those who are prone to hypercalcemia. Recombinant human erythropoietin subcutaneously and iron orally or intravenously are important treatments for anemia (399).

Clinical Characteristics

CRPS is characterized by pain, hyperesthesia, edema, cold or warm extremity, cyanosis, mottling of skin, limited ROM, and patchy bone demineralization. Adults with CRPS complain of hot and cold extremities, but kids more than likely have a cold cyanotic extremity (404).


As mentioned at the onset of this constitutional bone condition section, typically, these individuals have normal intelligence. They may, however, be perceived differently, especially if they are smaller than their chronological age. Age-appropriate interventions are key for this group. It is important to know the key features in these groups as well as serious complications. As these conditions generally have increased risk of atlantoaxial instability, these individuals should be restricted from contact sports and other high-risk activities (11).

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