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Syndromes 2

Summery

This is part 2 of the literature review on Syndromes by Pure Dentistry Dentists in Brisbane.

Differential Diagnosis:

Differential diagnosis for KS includes: Fragile X-syndrome, Kallman syndrome, Marfan syndrome and. 47 XXY trait is only seen in KS, therefore karyotyping can differentiate between KS and syndromes mentioned above. Furthermore, the characteristics of KS is different to the above-mentioned syndromes.

Fragile X syndrome:

  • also termed Martin-Bell syndrome or marker X syndrome
  • effects both men and women
  • Growth: Childhood growth is marked by an early growth spurt, but adult height is often average or slightly below average. Additionally, obesity during adolescence and early adulthood is common.
  • Statistically significant phenotypic characteristics of young males with fragile X syndrome include the presence of a hallucal crease (a single crease between the first and second toes), sensitivity to touch, and the inability to touch the tongue to the lips
  • A small subset of male patients may have obesity, poor linear growth, small hands and feet, and diffuse hyperpigmentation
  • Craniofacial: Adolescent and adult patients have a long, thin face with prominent ears, prominent foreheads, facial asymmetry, a head circumference higher than the 50th percentile, and a prominent jaw
  • The mouth has dental overcrowding and a high-arched palate
  • Ears are typically large and may protrude
  • Eyes: Strabismus is frequent; occasionally, nystagmus, astigmatism, and ptosis are present
  • Hands and feet: hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus; clubfeet may be present at birth
  • Pectus excavatum and scoliosis are frequent findings
  • Genitals: Macroorchidism is nearly universal in postpubertal males
  • During childhood, an increased incidence of inguinal hernias is reported
  • Cardiac: A heart murmur or click consistent with mitral valve prolapse

Marfan Syndrome

  • Connective tissue, autosomal dominant disorder
  • Myopia (nearsightedness)
  • Tall, thin, long arms, legs fingers and toes
  • Cardiac complications: aortic aneurysm, dilation, mitral valve prolapse
  • joint pain in older patients
  • Dyspnea, severe palpitations, and substernal pain in significant pectus excavatum
  • Breathlessness, often associated with chest pain, in spontaneous pneumothorax

Kallman syndrome

  • Can be seen in men and women
  • Hypogonadotropic hypogonadism
  • Anosmia (lack of sense of smell)
  • Infertility
  • No intellectual disability

Pathogenesis:

The X chromosome carries genes that have a role in many organ systems, for example, in testes function, brain development, and growth (Giedd et al. 2007).

Men with Klinefelter syndrome have a higher risk of:

  • autoimmune diseases
  • diabetes mellitus
  • osteopenia  and osteoporosis
  • tumors (breast and germ cells)
  • systemic lupus erythematosus
  • rheumatoid arthritis
  • Sjögren syndrome
  • cardiovascular disease,
  • lung disease and epilepsy

 

osteopenia  and osteoporosis can cause  increase in  fractures due to hypogonadism which reduces the physical exercise capacity and muscle strength. Testosterone replacement can increase bone mineral density (Groth et al. 2013).

Patients with KS are more frequently insulin resistant, obese and prone to develop type 2 diabetes mellitus (Salzano et al. 2016). This can be related to lower levels of testosterone and more abdominal adiposity in KS patients.

Bojesen et al. also reported higher incidence of metabolic syndrome and insulin resistance with KS compared to the control group (Bojesen et al. 2006).

 

In a group of ten obese KS patients with type 2 diabetes mellitus and erectile dysfunction, the addition of metformin and liraglutide induced weight loss and improved erectile function in the patients in which testosterone therapy alone was insufficient to achieve serum testestrone levels in the range of healthy men. Furthermore, the patients were able to reach glycemic targets and to lower weight, leading to a considerable improvement of erectile function (Giagulli et al. 2015).

A recent clinical study in Japan on men who underwent microdissection testicular sperm extraction showed negative correlations between gonadotropins and BMI in patients with KS. This finding may suggest an underlying suppressive effect on gonadotropin excretion, which is distinctive in obese patients with KS (Iwatsuki et al. 2017).

Early identification and anticipatory guidance are extremely helpful in Klinefelter syndrome. Management and treatment should focus on 3 major facets of the syndrome: hypogonadism, gynecomastia, and psychosocial problems.

Androgen (testosterone) replacement therapy is an important aspect of treatment. Historically, testosterone replacement was started at puberty, around age 12 years, with the dose increased over time, until it was sufficient to maintain age-appropriate serum concentrations of testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Regularly scheduled testosterone injections promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behaviour; and protect against precocious osteoporosis. In addition, there are the long-term beneficial effects of decreasing the risks of autoimmune disease and breast cancer. However, testosterone therapy does not treat infertility or gynecomastia (Visootsak and Graham 2006).

A study by Samango-Sprouse et al suggested that early hormonal therapy (EHT) can improve social behavior in boys with Klinefelter syndrome (Samango-Sprouse et al. 2015).

A double-blind, randomized trial by Ross et al of low-dose androgen treatment in prepubertal boys with KS found improvement at 24 months in visual-motor function,anxiety, depression, and social problems (Ross et al. 2017).

A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems. In children, early speech and language therapy is particularly helpful for developing skills in the understanding and production of more complex language.

Dental manifestations:

There have been several case reports that have found multiple missing teeth, small and peg shaped lateral incisors in KS patients.

Taurodontism is the most common dental manifestation of KS. Although the exact cause is unclear, it has been suggested that specific gene effects of chromosome X are involved (Varrela and Alvesalo 1988). Generalised disturbance of developmental homeostasis has been suggested by Witkop as a possible cause (Witkop et al. 1988).

In 1978 Komatz et al. reported taurodontism in 6 of the 31 cases (19.4%) with XXY KC. (Komatz et al. 1978). In 1980 Jasper and Witkop evaluated 9 male patients previously diagnosed as exhibiting aneuploidy of the X chromosome radiographically for taurodontic molars. Eight individuals exhibited taurodontism: six were judged hypo-, one meso-, and one hypertaurodontic. One individual was judged to exhibit a nontaurodontic dentition (Jaspers and Witkop 1980). This may result in more difficult root canal tretaments if needed.

The shape and size of the craniofacial complex in 35 adults with KS were analyzed cephalometrically and compared with 60 control males. Most of the differences were located in the cranial base, the cranial base angle. The length of the maxillary base was greater and more prognathic. The mandible was also longer and more prognathic (Brkic et al. 1994).

Ectodactyly- Ectodermal Dysplasia Clefting Syndrome

Description:
Ectodatyly Ectodermal Dysplasia Clefting Syndrome was first described in 1804 by Eckoldt and Martins. They reported patients having lobster-claw anomaly of their hands and feet, obstruction of nasolacrimal duct and cleft lip and palate. The name to this syndrome was given by Rudiger in 1970 (Rüdiger et al. 1970).

Other names:

  • Ectodatyly-ectodermal dysplasia- clefting syndrome
  • Ectodatyly-ectodermal dysplasia- orofacial clefts
  • ECC syndrome
  • Rudiger syndrome 1
  • WalkerClodius syndrome
  • Split hand–split foot–ectodermal dysplasia–cleft syndrome

Prevalence:

The occurrence of all three disorders in one, (ectrodactyly, ectodermal dysplasia, and cleft lip/palate) is very rare approximately 1.5/100 million (Rüdiger et al. 1970).

Genetics:

The inheritance is autosomal dominant, but sporadic and autosomal recessive traits have also been reported. Genetic studies have revealed that mutation in the TP63 or TP73L genes occur in these cases (Brunner et al. 2002)

Clinical characteristics:

EEC is characterized by the triad of (Rüdiger et al. 1970):

  • ectrodactyly (longitudinal deficiency of central digits) and syndactyly (fused digits) of hands and feet
  • ectodermal dysplasia
  • cleft palate and/or cleft lip

Other features noted in association with EEC include (Rosenmann et al. 1976):

  • vesicoureteral reflux
  • recurrent urinary tract infections
  • obstruction of the nasolacrimal duct
  • decreased pigmentation of the hair and skin
  • missing or abnormal teeth, enamel hypoplasia
  • absent punctae in the lower eyelids
  • photophobia
  • occasional cognitive impairment
  • kidney anomalies
  • conductive hearing loss

Although it is very rare to see all cardinal signs of EEC together, ectrodactyly appears to be the only constant component of this syndrome (Rosenmann et al. 1976). Not all 3 characteristic signs need to present to diagnose the condition (Kuster et al. 1985, Fryns et al. 1990).

Diagnosis:

Prenatal diagnosis can be done  based on identification of ectodactyly, cleft lip/palate or other associated anomalies which can be detected during routine ultrasound.

Genetic testing by detecting mutations in TP63 gene. Abnormal chromosomes that account for the phenotype also can be used for diagnosis

The only proven mutations known to underlie EEC in humans have been found in the TP63 gene (Brunner et al. 2002).

Diagnosis can also be made based on identification of characteristic symptoms, patient history, clinical examination and radiographic findings.

Patients with ectodermal dysplasia should have their salivary functions tested. It has been reported by Nordgarden et al. ectodermal dysplasia patients showed significant reduction in stimulated salivary flow rate. Reduced secretion of submandibular and/or parotid gland was also noticed (Nordgarden, Storhaug et al. 2003). lack of saliva may affect the types of prosthetics chosen, as well as predispose the patient to candida infections and caries (Pashayan, Pruzansky et al. 1974, Pries, Mittelman et al. 1974).

Dentists should also be aware of enamel hypoplasia associated with EEC. Preventive care to minimize caries is important. Reinforcement of oral hygiene which may need to be done by a carer, low fermentable carbohydrate diet advises and fluoride applications are important. These teeth can also be very sensitive.

Impaired vision and hearing should also be acknowledged in communicating with patient with EEC syndrome.

Dental manifestations and considerations:

  • Due to ectrodactyly holding the toothbrush is difficult which will compromise adequate oral hygiene (King et al. 1994).
  • Hypodontia and anodontia (Brill, Hsu et al. 1972, Crawford, Aldred et al. 1991).
  • Reduced growth rate and deficiency in the alveolar processes of the affected arch due to missing teeth (Johnson et al. 2002)
  • Microdontia (Pries et al. 1974)
  • Enamel hypoplasia (Brill et al. 1972)
  • Misshapen teeth (Crawford et al. 1991)
    • Conical
    • Tapered
  • Taurodontism (Crawford et al. 1991)
  • Xerostomia (Pashayan et al. 1974, Pries et al. 1974).

 

Below is a Panoramic radiograph of 17-year-old boy diagnosed with ectodermal dysplasia. Note lack of alveolar bone development caused by lack of tooth formation. Implant-supported fixed detachable prosthesis on mandibular arch, opposed by overdenture supported by retained natural teeth, was proposed treatment of choice (Hickey and Vergo 2001)

Differential Diagnosis:

  1. Ectrodactyly of the feet and cleft palate also knows as Patterson-Stevenson- Fontaine syndrome which  is a very rare syndrome characterized by abnormal development of the bones and tissues of the face (mandibulofacial dysostosis) and limb abnormalities. Physical features of this condition may include a recessed jaw (retrognathism), cleft palate, and anomalies of the external ears. Limb abnormalities may include the absence of toes, clefts in the feet, and fusion of toes together (syndactyly). These limb abnormalities together are known as split-foot deformity or ectrodactyly.
  2. Hay- Welles Syndrome or AEC syndrome – Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a form of ectodermal dysplasia, a group of about 150 conditions characterized by abnormal development of ectodermal tissues including the skin, hair, nails, teeth, and sweat glands.
  3. Ectrodactyly-cleft palate Syndrome (ECP Syndrome)- This syndrome combines ectrodactyly with cleft palate, without cleft lip or the ectodermal features that occur with the EEC syndrome
  4. Rapp-Hodgkin syndrome is a type of anhidrotic ectodermal dysplasia
  5. ADULT syndrome Acro–dermato–ungual–lacrimal–tooth syndrome is a rare autosomal dominant form of ectodermal dysplasia, a group of disorders that affects the hair, teeth, nails, sweat glands, and extremities . The lack of facial clefting and ankyloblepharon are important because they exist in ectrodactyly–ectodermal dysplasia–cleft syndrome (EEC) but not in ADULT syndrome.

Features such as conical shaped incisors, bud shaped molars and taurodontism can be seen on orthopantomogram. Contact points on teeth are usually apically displaced and this is more sever in male patients compared to females (Crawford et al. 1991).

Most common complaint in young patients with ectodermal dysplasia concern about the dental anomalities and facial appearance (Siegel and Potsic 1990). Consequently, the dentist, orthodontist or the maxillofacial surgeon are probably the first medical professionals to be confronted with complaints of this syndrome.

Missing teeth can have a significant effect on young patients emotionally, therefore beginning treatment for these patients before they start school is beneficial (Tanner 1988).

Nakata et al. and Prager et al. showed that the first molars, upper central incisors and upper and lower canines were the most stable tooth types and were the teeth most often present (Nakata  et al. 1980, Prager et al. 2006).

Options to replace missing teeth include:

Removable appliances such as partial denture, complete denture, overdenture can be used in early childhood. These appliances will need to be adjusted and modified as the child grows. Using primary teeth can help with a natural appearance of the denture (Pigno et al. 1996). In their adulthood they can choose a more fixed appliance if they wish.

 

Replacement of teeth by implants is usually restricted to patients with completed craniofacial growth, as they can act as ankylosed teeth and as the alveolus grows around it, the implant looks submerged. In a small number of paediatric patients suffering congenitally from severe hypodontia caused by syndromes such as ectodermal dysplasia, conventional prosthodontic rehabilitations are insufficient (Kramer et al. 2007). Guckes et al. has suggested remarkable benefits from implant supported oral rehabilitation during early childhood (Guckes et al. 2002). He conducted a prospective clinical trial in which he placed 264 implants in 51 patients with ectodermal dysplasia between the ages 8 and 68. They were restored with fixed-detachable or bar-clip overdenture. 91 % of the mandibular and 76% of the maxillary implants were successful.

Studies by Kearns et al. and Kramer et al. also showed successful outcome of placing implants in young children which resulted in improved oral function and had psychological benefits (Kearns  et al. 1999, Kramer et al. 2007)

Kramer et al. also suggested that anterior mandible seems to be the most suitable site for insertion of an implant and anterior maxilla should be avoided or at least not cross the midline. For optimal timing of placing an implant in a paediatric patient the status of skeletal growth and the degree of hypodontia should be considered (Kramer et al. 2007).

Below is photos of an Eight-year-old girl diagnosed with ectodermal dysplasia with associated cleft palate. B, Maxillary and mandibular overdentures in place, supported by existing teeth. Overdentures restored oral function and provided facial and psychosocial support. C, Same patient at age 18 years. D, Same patient after completion of periodontal surgery, root canal therapy on maxillary and mandibular anterior teeth, and posterior crowns in preparation for removable partial overdentures. E, Panoramic radiograph of patiencompletedreatment. F, Completed maxillofacial prosthetic treatment combining fixed prosthodontics with removable partial overdentures (Hickey and Vergo 2001).

References Cleidocranial Dysplasia:                                                                                                        

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References Turner syndrome and Noonan syndrome:

Al Alwan, I., et al. (2014). “Turner Syndrome Genotype and phenotype and their effect on presenting features and timing of Diagnosis.” Int J Health Sci (Qassim) 8(2): 195-202.

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References Klinefelter Syndrome:

Bojesen, A., et al. (2006). “Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses.” J Clin Endocrinol Metab 91(4): 1254-1260.

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