Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern, and by incomplete penetration of the trait.

Hypophosphatasia is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities. The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo-Saxon origin. The frequency of mild hypophosphatasia is more challenging to assess because the symptoms may escape notice or be misdiagnosed. The highest incidence of hypophosphatasia has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns exhibits severe disease. Hypophosphatasia is considered particularly rare in people of African ancestry in the U.S.

Vitamin D natural selection hypotheses:

Rickets is often a result of vitamin D3 deficiency. The vitamin D natural selection hypothesis suggests that vitamin D production from sunlight is a selective force for human skin color variation. The correlation between human skin color and latitude is thought to be the result of positive selection to varying levels of solar ultraviolet radiation. Northern latitudes have selection for lighter skin that allows UV rays to produce vitamin D from 7-dehydrocholesterol. Conversely, latitudes near the equator have selection for darker skin that can block the majority of UV radiation to protect from toxic levels of vitamin D, as well as skin cancer.

An anecdote often cited to support this hypothesis is that Arctic populations whose skin is relatively darker for their latitude, such as the Inuit, have a diet that is historically rich in vitamin D. Since these people acquire vitamin D through their diet, there is not a positive selective force to synthesize vitamin D from sunlight.

Environment mismatch:

Ultimately, vitamin D deficiency arises from a mismatch between a populations previous evolutionary environment and the individual’s current environment. This risk of mismatch increases with advances in transportation methods and increases in urban population size at high latitudes.

Similar to the environmental mismatch when dark-skinned people live at high latitudes, Rickets can also occur in religious communities that require long garments with hoods and veils. These hoods and veils act as sunlight barriers that prevent individuals from synthesizing vitamin D naturally from the sun.

In a study by Mithal et al., Vitamin D insufficiency of various countries was measured by lower 25-hydroxyvitamin D. 25(OH)D is an indicator of vitamin D insufficiency that can be easily measured. These percentages should be regarded as relative vitamin D levels, and not as predicting evidence for development of rickets.

Asian immigrants living in Europe have an increased risk for vitamin D deficiency. Vitamin D insufficiency was found in 40% of non-Western immigrants in the Netherlands, and in more than 80% of Turkish and Moroccan immigrants.

The Middle East, despite high rates of sun-exposure, has the highest rates of rickets worldwide. This can be explained by limited sun exposure due to cultural practices and lack of vitamin D supplementation for breast-feeding women. Up to 70% and 80% of adolescent girls in Iran and Saudi Arabia, respectively, have vitamin D insufficiency. Socioeconomic factors that limit a vitamin D rich diet also plays a role.

In the United States, vitamin D insufficiency varies dramatically by ethnicity. Among males aged 70 years and older, the prevalence of low serum 25(OH) D levels was 23% for non-Hispanic whites, 45% for Mexican Americans, and 58% for non-Hispanic blacks. Among women, the prevalence was 28.5%, 55%, and 68%, respectively.

A systematic review published in the Cochrane Library looked at children up to three years old in Turkey and China and found there was a negative association between vitamin D and rickets. In Turkey children getting vitamin D had only a 4% chance of developing rickets compared to children who received no medical intervention. In China, a combination of vitamin D, calcium and nutritional counseling was linked to a decreased risk of rickets.

With this evolutionary perspective in mind, parents can supplement their nutritional intake with vitamin D enhanced beverages if they feel their child is at risk for vitamin D deficiency,

All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans (ALPL; OMIM#171760). Approximately 204 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression, and there appears to be a correlation between genotype and phenotype in hypophosphatasia”. Mutation analysis is possible and available in 3 laboratories.

Maternal deficiencies may be the cause of overt bone disease from before birth and impairment of bone quality after birth. The primary cause of congenital rickets is vitamin D deficiency in the mother's blood, which the baby shares. Vitamin D ensures that serum phosphate and calcium levels are sufficient to facilitate the mineralization of bone. Congenital rickets may also be caused by other maternal diseases, including severe osteomalacia, untreated celiac disease, malabsorption, pre-eclampsia, and premature birth. Rickets in children is similar to osteoporosis in the elderly, with brittle bones. Pre-natal care includes checking vitamin levels and ensuring that any deficiencies are supplemented.

Also exclusively breast-fed infants may require rickets prevention by vitamin D supplementation or an increased exposure to sunlight.

In sunny countries such as Nigeria, South Africa, and Bangladesh, there is sufficient endogenous vitamin D due to exposure to the sun. However, the disease occurs among older toddlers and children in these countries, which in these circumstances is attributed to low dietary calcium intakes due to a mainly cereal-based diet.

Those at higher risk for developing rickets include:

- Breast-fed infants whose mothers are not exposed to sunlight

- Breast-fed infants who are not exposed to sunlight

- Breast-fed babies who are exposed to little sunlight

- Adolescents, in particular when undergoing the pubertal growth spurt

- Any child whose diet does not contain enough vitamin D or calcium

The life expectancy in alpha-mannosidosis is highly variable. Individuals with early onset severe disease often do not survive beyond childhood, whereas those with milder disorders may survive well into adult life.

The worldwide incidence of alpha-mannosidosis is in the range of 1 per 500,000 to 1 per 1,000,000. Mannosidosis is found in all ethnic groups in Europe, America, Africa, and Asia.

Although the epidemiologic data indicate that all variants of normal growth are twice as common in boys as in girls, referrals for short stature reflect an even more divergent sex ratio. This likely reflects greater concern about males who are shorter than their peers or who have delayed sexual development.

No racial bias has been identified. Patterns of growth consistent with CDGP occur in infants as young as 3–6 months. However, individuals often do not seek medical attention until puberty, when lack of sexual development becomes a concern and discrepancy in height from peers is magnified by the delay in pubertal growth spurt.

CDGP is not associated with increased mortality because it is a variant of normal growth rather than a disease. However, in some affected individuals, it can be associated with significant psychological stress, resulting in poor self-image and social withdrawal. In recent years, researchers have also found that individuals with CDGP may be at increased risk for reduced bone mass in adulthood because of the delay in sex steroid influence on bone accrual during adolescence.

A 2001 study followed up on 50 patients. Of these 38% died in childhood while the rest suffered from problems with morbidity.

The proposed mechanism involves shear stress and lack of displacement due to the periosteum that is relatively strong compared to the elastic bone in young children.

Hypocementosis is a reduction in the amount of cementum on a tooth root. It is a feature of conditions such as cleidocranial dysplasia and hypophosphatasia.

Mutations in the "HADHA" gene lead to inadequate levels of an enzyme called long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase, which is part of a protein complex known as mitochondrial trifunctional protein. Long-chain fatty acids from food and body fat cannot be metabolized and processed without sufficient levels of this enzyme. As a result, these fatty acids are not converted to energy, which can lead to characteristic features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, retina, and muscles, causing more serious complications.

Copenhagen disease, sometimes known as Copenhagen syndrome, refers to progressive non-infectious anterior vertebral fusion, a rare childhood disease of unknown cause.

It affects the lower back, as can be seen on MRI scans. It is characterised by a lack of disc height of the vertebrae.

Toddler's fractures or childhood accidental spiral tibial (CAST) fractures are bone fractures of the distal (lower) part of the shin bone (tibia) in toddlers (aged 9 months-3 years) and other young children (less than 8 years). The fracture is found in the distal two thirds of the tibia in 95% of cases, is undisplaced and has a spiral pattern. It occurs after low-energy trauma, sometimes with a rotational component.

If a metabolic crisis is not treated, a child with VLCADD can develop: breathing problems, seizures, coma, sometimes leading to death.

Growth hormone deficiency in childhood commonly has no identifiable cause (idiopathic), and adult-onset GHD is commonly due to pituitary tumours and their treatment or to cranial irradiation. A more complete list of causes includes:

- mutations of specific genes (e.g., GHRHR, GH1)

- congenital diseases such as Prader-Willi syndrome, Turner syndrome, or short stature homeobox gene (SHOX) deficiency

- congenital malformations involving the pituitary (e.g., septo-optic dysplasia, posterior pituitary ectopia)

- chronic renal insufficiency

- intracranial tumors in or near the sella turcica, especially craniopharyngioma

- damage to the pituitary from radiation therapy to the head (e.g. for leukemia or brain tumors), from surgery, from trauma, or from intracranial disease (e.g. hydrocephalus)

- autoimmune inflammation (hypophysitis)

- ischemic or hemorrhagic infarction from low blood pressure (Sheehan syndrome) or hemorrhage pituitary apoplexy

There are a variety of rare diseases which resemble GH deficiency, including the childhood growth failure, facial appearance, delayed bone age, and low IGF levels. However, GH testing elicits normal or high levels of GH in the blood, demonstrating that the problem is not due to a deficiency of GH but rather to a reduced sensitivity to its action. Insensitivity to GH is traditionally termed Laron dwarfism, but over the last 15 years many different types of GH resistance have been identified, primarily involving mutations of the GH binding protein or receptors.

Adducted thumb syndrome recessive form is a rare disease affecting multiple systems causing malformations of the palate, thumbs, and upper limbs. The name Christian syndrome derives from Joe. C. Christian, the first person to describe the condition. Inheritance is believed to be autosomal recessive, caused by mutation in the CHST14 (carbohydrate sulfotransferase 14) gene.

Clouston's hidrotic ectodermal dysplasia (also known as "Alopecia congenita with keratosis palmoplantaris," "Clouston syndrome," "Fischer–Jacobsen–Clouston syndrome," "Hidrotic ectodermal dysplasia," "Keratosis palmaris with drumstick fingers," and "Palmoplantar keratoderma and clubbing") is caused by mutations in a connexin gene, GJB6 or connexin-30, characterized by scalp hair that is wiry, brittle, and pale, often associated with patchy alopecia.

Treatment of manifestations: special hair care products to help manage dry and sparse hair; wigs; artificial nails; emollients to relieve palmoplantar hyperkeratosis.

Kleefstra syndrome affects males and females equally and approximately, 75% of all documented cases are caused by Eu-HMTase1 disruptions while only 25% are caused by 9q34.3 deletions. There are no statistics on the effect the disease has on life expectancy due to the lack of information available.

As an adult ages, it is normal for the pituitary to produce diminishing amounts of GH and many other hormones, particularly the sex steroids. Physicians therefore distinguish between the natural reduction in GH levels which comes with age, and the much lower levels of "true" deficiency. Such deficiency almost always has an identifiable cause, with adult-onset GHD "without" a definable cause ("idiopathic GH deficiency") extremely rare. GH does function in adulthood to maintain muscle and bone mass and strength, and has poorly understood effects on cognition and mood.

This syndrome is associated with microcephaly, arthrogryposis and cleft palate and various craniofacial, respiratory, neurological and limb abnormalities, including bone and joint defects of the upper limbs, adducted thumbs, camptodactyly and talipes equinovarus or calcaneovalgus. It is characterized by craniosynostosis, and myopathy in association with congenital generalized hypertrichosis.

Patients with the disease are considered intellectually disabled. Most die in childhood. Patients often suffer from respiratory difficulties such as pneumonia, and from seizures due to dysmyelination in the brain's white matter. It has been hypothesized that the Moro reflex (startle reflex in infants) may be a tool in detecting the congenital clapsed thumb early in infancy. The thumb normally extends as a result of this reflex.

Prognosis varies widely depending on severity of symptoms, degree of intellectual impairment, and associated complications. Because the syndrome is rare and so newly identified, there are no long term studies.

Due to its recent discovery, there are currently no existing treatments for Kleefstra syndrome.

Typically, initial signs and symptoms of this disorder occur during infancy and include low blood sugar (hypoglycemia), lack of energy (lethargy), and muscle weakness. There is also a high risk of complications such as liver abnormalities and life-threatening heart problems. Symptoms that begin later in childhood, adolescence, or adulthood tend to be milder and usually do not involve heart problems. Episodes of very long-chain acyl-coenzyme A dehydrogenase deficiency can be triggered by periods of fasting, illness, and exercise.

It is common for babies and children with the early and childhood types of VLCADD to have episodes of illness called metabolic crises. Some of the first symptoms of a metabolic crisis are: extreme sleepiness, behavior changes, irritable mood, poor appetite.

Some of these other symptoms of VLCADD in infants may also follow: fever, nausea, diarrhea, vomiting, hypoglycemia.