NORD is very grateful Bruce D. Gelb, MD, The Gogel Family Professor of Child Health and Development, Professor of Pediatrics and Genetics & Genomic Sciences, Director, Child Health and Development Institute, Mount Sinai School of Medicine, for assistance in the preparation of this report.
Synonyms of Kenny-Caffey Syndrome
- dwarfism, cortical thickening of tubular bones & transient hypocalcemia
- Kenny-Caffey syndrome, dominant type
- No subdivisions found.
Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare hereditary skeletal disorder characterized by thickening of the long bones, thin marrow cavities in the bones (medullary stenosis), and abnormalities affecting the head and eyes. Most cases are obvious at birth (congenital). The primary outcome of KCS2 is short stature. Intelligence is usually normal. Individuals with KCS may also have recurrent episodes of low levels of calcium in the blood stream (hypocalcemia) that is caused by insufficient production of parathyroid hormones (hpoparathyroidism). In most cases, KCS2 is an autosomal dominant genetic disorder.
KSC2 is present at birth (congenital) and low birth weight may be one of the first symptoms. This extremely rare genetic disorder is characterized by abnormalities affecting the skeleton, the head, and the eyes. Recurrent episodes of unusually low levels of calcium (hypocalcemia) in the blood are common. Most affected individuals, exhibit short stature of adult height ranging from 48 to 59 inches. Intelligence is usually normal.
KCS2 usually affects several bones of the body. Affected individuals may have thickened outer layers (cortexes) of various long bones, and abnormally thin marrow cavities (medullary stenosis). Some individuals may also have abnormal hardening of some bones (osteosclerosis).
KCS2 also affects the head and face. The anterior fontanel is a soft, membrane-covered area between the bones of an infant's skull that usually closes about 18 months after birth. However, in KCS2, the anterior fontanel is abnormally large, closes late, and a fibrous joint between the bones in the forehead (metopic suture) is spaced wider than usual. As a result, affected infants have an abnormally large head circumference (macrocephaly) with a prominent forehead.
Several abnormalities of the eyes are also associated with KCS2. Affected individuals may have unusually small eyes (microphthalmia), leakage of cerebrospinal fluid into the optic disk of the eye may cause swelling of the disk (papilledema), and/or farsightedness (hyperopia). In some cases of this disorder, nearsightedness (myopia) has been observed. One case reported in the medical literature noted retinal and corneal calcification. Another case had bilateral optic atrophy.
Episodes of abnormally low levels of calcium in the blood (hypocalcemia) are prevalent in individuals, especially infants, affected by KCS2. Onset of hypocalcemia is usually within two to three months after birth. Other episodes may occur in relation to stress or may follow surgery or illness in an adult. Hypocalcemia is not permanent (transient) and may be caused by insufficient production of parathyroid hormones (hypoparathyroidism). These hormones, along with vitamin D and the hormone calcitonin, regulate the levels of calcium in the blood. The lack of the parathyroid hormones may be due to improper function or absence of the parathyroid glands in people with KCS2. Symptoms of hypoparathyroidism include weakness, muscle cramps; excessive nervousness; loss of memory; headaches, and abnormal sensations such as tingling, burning, and numbness of the hands. (For more information about "Hypoparathyroidism," please see the Related Disorders section of this report.)
Low levels of calcium in the blood may also cause a condition called tetany, which is characterized by muscle cramps and periods of high-pitched respiration (stridor). Individuals with KCS2 may also exhibit abnormally low levels of phosphates in the blood (hypophosphatemia), low levels of a hormone that acts to reduce the blood level of calcium (calcitonin), low levels of circulating red blood cells (anemia), and seizures.
People affected by the recessive form of KCS2 have most of the above-mentioned abnormalities and symptoms. They may also exhibit liver disease during the first month of life (neonatal period), abnormally low levels of a certain type of white blood cell (neutropenia), improper function of another type of white blood cell (T-cells), and/or underdeveloped (hypoplastic), malformed nails.
In most cases, KCS2 is an autosomal dominant genetic disorder. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the gender of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.
X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.
Investigators have determined that the recessive form of Kenny-Caffey syndrome is the same disorder as Hypoparathyroidism-retardation-dysmophic (HRD) syndrome, which is also known as Sanjad-Sakati syndrome. HRD is an extremely rare disorder characterized by hypoparathyroidism that is present at birth (congenital); growth retardation, mental retardation; and characteristic facial abnormalities. Such facial features may include deep-set eyes, abnormally thin upper lip, abnormally small jaw (micrognathia), and a depressed bridge of the nose. Affected individuals may also have skeletal defects, abnormally thin marrow cavities (medullary stenosis), and abnormally low levels of calcium in the blood (hypocalcemia). HRD syndrome is inherited as an autosomal recessive trait. HRD syndrome is caused by disruption or changes (mutations) of the tubulin-specific chaperone E (TBCE) gene located on the long arm (q) of chromosome 1 (1q42-q43). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 1q42" refers to band 42 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Some cases of autosomal recessive Kenny-Caffey syndrome/HRD syndrome have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
KCS2 is an extremely rare skeletal disorder that affects males and females in equal numbers. Fewer than 60 cases have been reported in the medical literature. Onset of hypocalcemia is usually within two to three months of life; the hypocalcemia is not permanent (transient). In an adult, episodes of hypocalcemia may be due to stress or follow surgery or illness. KCS2 was first described in the medical literature in 1966.
Symptoms of the following disorders can be similar to those of Kenny-Caffey syndrome type 2. Comparisons may be useful for a differential diagnosis:
Kenny-Caffey syndrome type 1 is the recessive form of KCS, and is also called hypoparathyroidism-retardation-dysmophic (HRD) syndrome or Sanjad-Sakati syndrome. HRD is an extremely rare disorder characterized by hypoparathyroidism that is present at birth (congenital); growth retardation,intellectual disability ; and characteristic facial abnormalities. Such facial features may include deep-set eyes, abnormally thin upper lip, abnormally small jaw (micrognathia), and a depressed bridge of the nose. Affected individuals may also have skeletal defects, abnormally thin marrow cavities (medullary stenosis), and abnormally low levels of calcium in the blood (hypocalcemia). HRD is caused by disruption or changes (mutations) of the tubulin-specific chaperone E (TBCE) gene.
Osteopetrosis is a rare genetic skeletal disorder characterized by the abnormal hardening of bones. Symptoms may include thickening of the bones, increased density of the bone marrow, delayed closure of a soft spot of an infant's skull (anterior fontanel), and anemia. The basic defect in bone growth involves insufficient production of intercellular bone tissue by cells called osteoblasts. These osteoblasts aid in the production of bone by maintaining a balance between formation and loss of calcium in the bone. Osteopetrosis can be inherited as either an autosomal dominant or recessive trait. (For more information on this disorder, choose "Osteopetrosis" as your search term in the Rare Disease Database.)
Pycnodysostosis is a rare disorder characterized by short stature and increased density of the bones. Individuals with this disorder typically have short arms and legs with broad hands and feet. Delayed closure of the space between the bones of the skull (fontanels) typically occurs. Additional features may include an unusually large head (macrocephaly) with a small face, a receding chin with a small jaw, brittle finger and toe nails, a bluish discoloration of the whites of the eyes (blue sclerae), dental abnormalities, and/or an underdeveloped collarbone. Pycnodysostosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Pycnodysostosis" as your search term in the Rare Disease Database.)
A large anterior fontanel that closes late is also seen in cleidocranial dysplasia and congenital hypoparathyroidism. (For more information on these disorders, choose "Cleidocranial Dysplasia" and "Hypoparathyroidism" as your search terms in the Rare Disease Database.)
The following disorder may be associated with KCS2 as a secondary characteristic. It is not necessary for a differential diagnosis:
Hypoparathyroidism is a rare endocrine disorder characterized by low levels of calcium in the blood. It is caused by insufficient production of parathyroid hormones. These hormones, along with vitamin D and the hormone calcitonin, regulate the levels of calcium in the blood. The lack of production of parathyroid hormones may be due to improper function or absence of the parathyroid glands. Symptoms of hypoparathyroidism include weakness; muscle cramps; excessive nervousness; loss of memory; headaches; and abnormal sensations such as tingling, burning, and numbness of the hands. The exact cause of hypoparathyroidism is not fully understood. (For more information on this disorder, choose "Hypoparathyroidism" as your search term in the Rare Disease Database.)
The diagnosis of KCS2 may be confirmed by x-ray studies of the skeleton that reveal distinctive thickening of the outer layers (cortexes) of long bones along with unusually thin marrow cavities. Blood tests can detect episodes of low levels of calcium in the blood (hypocalcemia).
The treatment of KCS2 is directed toward the specific symptoms that are apparent in each individual. Vitamin D and calcium have been prescribed for and proven effective in treating hypocalcemia. If anemia occurs, iron supplements may be prescribed. People with KCS2 should be monitored regularly by an eye doctor (ophthalmologist) who is familiar with the eye abnormalities associated with this syndrome.
Genetic counseling is recommended for affected individuals and their families. A supportive team approach for children with KCS2 may be of benefit. Such a team approach may include physical therapy and other medical, social, or vocational services. Other treatment is symptomatic and supportive.
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Tollfree: (800) 411-1222
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Organizations related to Kenny-Caffey Syndrome
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