Hypochondroplasia - GeneReviews® - NCBI Bookshelf
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in Short stature is common (if not treated with growth hormone); testing have been proposed based on analysis of diagnostic criteria met in .. Males may have a characteristic appearance (large head, long face. A description of tropes appearing in Meet the Robinsons. Disney's 47th animated feature, Tiny: "I have a big head and little arms! I'm just not sure how well this. Large head (macrocephaly) with relatively normal facies . Young children and adults often have a thick, muscular appearance and may be described as "stocky. . Thanatophoric dysplasia (TD) is a short-limb dwarfism syndrome that is .. Jones SM, Robinson LK, Sperrazza R. Prenatal diagnosis of.
In general, it appears that the phenotypes of individuals diagnosed with hypochondroplasia who have FGFR3 pathogenic variants c. More recently, both Heuertz et al  and Song et al  reported that a p. There is still no consensus as to which specific clinical features distinguish hypochondroplasia due to FGFR3 p. Fano et al  reported that affected individuals with a head circumference greater than 1.
LysThr have a higher likelihood of developing acanthosis nigricans see Clinical DescriptionEndocrinology. Pathogenic variants resulting in p. LysGln are associated with a slightly milder skeletal phenotype than pathogenic variants resulting in p. Bellus et al  reported six individuals with p.
LysGly who had a significantly lower average height deficit than 36 individuals with p.
In addition, the L1: Mortier et al  and Thauvin-Robinet et al  reported on families with p. The phenotype in both families was relatively mild, with heights overlapping the lower end of the normal range for age, mild disproportion of the limbs, and macrocephaly. Somatic mosaicism has not been reported in hypochondroplasia.
Penetrance Because of evidence that the height range in hypochondroplasia may overlap that of the normal population, individuals with hypochondroplasia may not be recognized as having a skeletal dysplasia unless an astute physician recognizes their disproportionate short stature.
However, there have been no reports of individuals with an FGFR3 pathogenic variant without demonstrable radiographic changes compatible with hypochondroplasia or one of the other phenotypes known to be associated with pathogenic variants in this gene see Genetically Related Disorders.
Anticipation Genetic anticipation is not known to occur in hypochondroplasia. Ascertainment of cases is problematic as it is thought that many affected individuals present with no symptoms other than short stature and do not seek medical intervention.
However, it is generally agreed that hypochondroplasia is a relatively common skeletal dysplasia that may approach the prevalence of achondroplasia i. In addition, simplex cases affected individuals with no family history of hypochondroplasia have been associated with advanced paternal age. Simplex cases of hypochondroplasia caused by the FGFR3 p. AsnLys pathogenic variant are probably not as common as simplex cases of achondroplasia, given the fact that a transition at a CpG dinucleotide is the most common cause of the achondroplasia -causing p.
GlyArg change, while both pathogenic variants leading to p. AsnLys result from transversions not associated with CpG dinucleotides. Thanatophoric dysplasia TD is a short-limb dwarfism syndrome that is usually lethal in the perinatal period. TD is divided into type I, characterized by micromelia with bowed femurs and, uncommonly, the presence of cloverleaf skull deformity kleeblattschaedel of varying severity; and type II, characterized by micromelia with straight femurs and uniform presence of moderate-to-severe cloverleaf skull deformity.
Other features common to type I and type II include: Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported. It should be noted that mild cases of achondroplasia caused by FGFR3 p. AsnLys may have very similar clinical presentations and are thus easily confused.
Pierre Robin syndrome
Therefore, it is important to test for both FGFR3 pathogenic variants resulting in p. AsnLys and both pathogenic variants resulting in p. The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans ANand Muenke syndrome isolated coronal synostosis caused by the p.
Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Meet the Robinsons / Disney - TV Tropes
LysMet [ Bellus et alTavormina et al ]. Differential Diagnosis Numerous forms of skeletal dysplasia with disproportionate limbs are recognized and are characterized by clinical and radiologic features that distinguish them from hypochondroplasia and achondroplasia. Many of these disorders are quite rare.Meet the Robinsons
The diagnosis of hypochondroplasia is seldom made at birth unless a prior family history exists. Most affected individuals present with short stature as toddlers or young school-age children. Inappropriate diagnoses of hypochondroplasia are often made because the disorder is considered to be relatively common and the radiologic features are variable and may be subtle.
The following conditions may be confused with hypochondroplasia: Mild forms of metaphyseal chondrodysplasias Mild forms of mesomelic dwarfism Mild forms of spondyloepiphyseal-metaphyseal dysplasias Pseudohypoparathyroidism and pseudopseudohypoparathyroidism see Disorders of GNAS Inactivation Short stature caused by disturbances in the growth hormone axis Constitutive short stature Hypochondroplasia-achondroplasia complex FGFR3 p.
The skeletal phenotype is more severe than typically found in achondroplasia, but unlike homozygous achondroplasia, is not uniformly lethal. Life span, however, may be decreased. Ross et al  described the phenotype in one child with compound heterozygosity for Leri-Weil dyschondrosteosis and hypochondroplasia.
This child inherited both a SHOX deletion and the p. AsnLys FGFR3 pathogenic variantand had severe short stature with both rhizomelic and mesomelic shortening of the limbs. Management Evaluations Following Initial Diagnosis Evaluation of children with hypochondroplasia usually does not differ significantly from the evaluation of children with normal stature except for genetic counseling issues and dealing with parental concerns about short stature.
However, because the phenotype of FGFR3 hypochondroplasia may overlap with that of achondroplasia, recommendations for the management of achondroplasia as outlined by the American Academy of Pediatrics Committee on Genetics [ Trotter et al ] should be considered in children with hypochondroplasia who exhibit more severe phenotypic features.
These recommendations include but are not limited to the following: Clinical genetics consultation Measurement of height, weight, and head circumference and plotting on achondroplasia-standardized growth curves Neurologic examination for signs of spinal cord compression, with referral to a pediatric neurologist or neurosurgeon if needed Screening developmental assessment History for evidence of sleep apnea, with formal sleep study if suggestive MRI or CT examination of the foramen magnum if clinical findings of severe hypotonia, spinal cord compression, or central sleep apnea as demonstrated through a sleep study are present Evaluation for thoracic or lumbar gibbus in the presence of truncal weakness Examination for leg bowing, with orthopedic referral if bowing interferes with walking Speech evaluation at diagnosis or by age two years Observation for symptoms suggestive of epilepsy, with referral to a pediatric neurologist when indicated Treatment of Manifestations Management of short stature is influenced by parental expectations and concerns.
Final adult height in hypochondroplasia is considerably greater than that achieved in achondroplasia and therefore, functional limitations in society e. One reasonable approach is to address the parents' expectations and prejudices regarding the height of their child rather than attempting to treat the child. Developmental intervention and special educational input are appropriate, as indicated by deficiencies. The usual neurosurgical approach to spinal stenosis is laminectomy.
The L level most commonly required decompression. Making the family aware of support groups, such as the Little People of America Inc. LPAcan result in assistance with adaptation of the affected individual and the family to short stature through peer support, personal example, and social awareness programs. The LPA offers information on employment, education, disability rights, adoption of children of short stature, medical issues, suitable clothing, adaptive devices, and parenting through local meetings, workshops, seminars, and a national newsletter.
Seizure disorders should be treated in the standard manner. Prevention of Secondary Complications Standard management of frequent middle ear infections Consideration of surgery if neurologic status is affected by spinal cord compression Surveillance Height, weight, and head circumference should be monitored using achondroplasia-standardized growth curves. Neurologic examination for signs of spinal cord compression should be performed at routine well-child visits, with referral to a pediatric neurologist if needed.
History for evidence of sleep apnea should be taken at routine visits, with formal sleep study obtained when indicated. MRI or CT examination of the foramen magnum is indicated if there is evidence of severe hypotonia, spinal cord compression or central sleep apnea. Affected individuals should be evaluated for emerging leg bowing at routine visits, with orthopedic referral if bowing interferes with walking.
Social adjustment should be monitored. Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Pregnancy Management There is a paucity of literature regarding pregnancy management in women with skeletal dysplasias.
However, a number of women with hypochondroplasia have had unremarkable pregnancies and deliveries. In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size. Epidural or spinal anesthetic can be utilized, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy.
If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses. Therapies Under Investigation Growth hormone therapy. Trials of growth hormone therapy in hypochondroplasia have shown mixed results.
Meyer et al  emphasized the importance of considering pubertal development in assessing the response to growth hormone stimulation testing. Tanaka et al  reported data suggesting that children with hypochondroplasia may have a greater response to growth hormone therapy than children with achondroplasia. Their mean height increased 1. Rothenbuhler et al  treated six children with hypochondroplasia confirmed FGFR3 p. AsnLys substitution, mean age 2.
Their mean height SDS increased by 1. Since data about final adult height in growth hormone-treated individuals with hypochondroplasia are not available, the ultimate success of this approach remains uncertain.
Growth hormone therapy should still be considered experimental and controversial in this condition. Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for more than 15 years. Nevertheless, the procedure is very invasive and entails considerable disability and discomfort over a long period of time. While some advocate performing the procedure during childhood, many pediatricians, geneticists, and ethicists advocate postponement until adolescence, when the affected individual is able to make an informed decision.
Surgical limb lengthening is controversial, but is achieving greater acceptance with fewer complications as larger numbers of operations have been performed. Genetic Counseling Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. Mode of Inheritance Hypochondroplasia is inherited in an autosomal dominant manner.
Risk to Family Members Parents of a proband The majority of individuals with hypochondroplasia have parents of average stature and represent simplex occurrences caused by a de novo pathogenic variant ; however, in some instances, one or both parents have hypochondroplasia. There appears to be a paternal age effect in some simplex occurrences of hypochondroplasia [ Walker et al ].
However, association with gene loci 2q Diagnosis[ edit ] The syndrome is generally diagnosed clinically shortly after birth. The infant usually has respiratory difficulty, especially when supine. The cleft palate is often U-shaped and wider than in cleft palate that is not associated with this syndrome. Management[ edit ] The goals of treatment in infants with Robin sequence focus upon breathing and feeding, and optimizing growth and nutrition despite the predisposition for breathing difficulties.
If there is evidence of airway obstruction snorty breathing, apnea, difficulty taking a breath, or drops in oxygenthen the infant should be placed in the sidelying or prone position, which helps bring the tongue base forward in many children.
In a separate study of children with the clinical diagnosis of PRS managed at 2 different hospitals in Boston Evans et al. Because reflux of acidic contents in the posterior pharynx and upper airway can intensify the symptoms of Robin sequence, specifically by worsening airway obstruction, it is important to maximize treatment for GER in children with PRS and reflux symptoms.
In nasopharyngeal cannulation or placement of the nasopharyngeal airway or tubethe infant is fitted with a blunt-tipped length of surgical tubing or an endotracheal tube fitted to the childwhich is placed under direct visualization with a laryngoscope, being inserted into the nose and down the pharynx or throatending just above the vocal cords.
Surgical threads fitted through holes in the outside end of the tube are attached to the cheek with a special skin-like adhesive material called 'stomahesive', which is also wrapped around the outside end of the tube but not over the opening at the end to keep the tube in place. This tube or cannula, which itself acts as an airway, primarily acts as a sort of "splint" which maintains patency of the airway by keeping the tongue form falling back on the posterior pharyngeal wall and occluding the airway, therefore preventing airway obstruction, hypoxia and asphyxia.
Nasopharyngeal airways are not available at every center, however, when available, nasopharyngeal cannulation should be favored over the other treatments mentioned in this article, as it is far less invasive; it allows the infant to feed without the further placement of a nasogastric tube. This treatment may be utilized for multiple months, until the jaw has grown enough so that the tongue assumes a more normal position in the mouth and airway at birth, the jaws of some infants are so underdeveloped that only the tip of the tongue can be seen when viewed in the throat.
Some institutions discharge the infant home with a nasopharyngeal tube in place Citation: Distraction osteogenesis DOalso called a "Mandibular Distraction", can be used to correct abnormal smallness of one or both jaws seen in patients with Robin Sequence.
Enlargement of the lower jaw brings the tongue forward, preventing it from obstructing the upper airway. The process of DO begins with preoperative assessment. Doctors use three-dimensional imaging to identify the parts of the patient's facial skeleton that need repositioning and determine the magnitude and direction of distraction. They may then select the most appropriate distraction device or sometimes have custom devises fabricated.
When possible, intraoral devices are used. DO surgery starts with an osteotomy surgical division or sectioning of bone followed by the distraction device being placed under the skin and across the osteotomy. A few days later, the two ends of the bone are very gradually pulled apart through continual adjustments that are made to the device by the parents at home.
This gradual distraction leads to formation of new bone between the two ends. After the process is complete, the osteotomy is allowed to heal over a period of six to eight weeks. A small second surgery is then performed to remove the device.