CASE STUDY
Kabuki syndrome: A challenge for the primary care provider Bonnie Crane, MSN, PNP (Pediatric Clinical Education Coordinator)1 , Patricia T. Alpert, DrPH, MSN, FNP-BC, PNP-BC, CNE, FAANP (Associate Professor & Chair of the Physiologic Department)2 , Dianne Cyrkiel, MSN, PNP-C (Instructor)2 , & Alan Jauregui, MD, MSN, FNP (Instructor)2 1 2
Sunrise Children’s Hospital, Las Vegas, Nevada School of Nursing, University of Nevada, Las Vegas, Nevada
Keywords Developmental delay; genetics; primary care; syndromes. Correspondence Patricia T. Alpert, DrPH, MSN, FNP-BC, PNP-BC, CNE, FAANP, Associate Professor & Chair of the Physiologic Department, School of Nursing, University of Nevada, Las Vegas, 4505 Maryland Parkway, Box 453018, Las Vegas, NV 89154-3018. Tel: 702-895-3810; Fax: 702-895-4807; E-mail: [email protected] Received: August 2011; accepted: January 2012 doi: 10.1002/2327-6924.12044
Abstract Purpose: Using a case format, the pathogenesis, clinical manifestations, diagnosis, and management of Kabuki syndrome, a rare genetic condition, is presented. Nurse practitioners (NPs) may encounter patients presenting to the primary care setting with this rare syndrome; understanding this condition may help them to better care for these patients. Data source: A case presentation of a pediatric patient supported by the currently available literature from multiple health and medial databases. Conclusion: Kabuki syndrome is a rare phenomenon that occurs in 1 in every 32,000 births. A diagnosis of this syndrome may take several months to years because there are no specific tests, and the physical features may be subtle at birth, becoming more pronounced over a period of time during childhood. The degree of disease severity varies widely. Implications for practice: Understanding this syndrome increases the NP’s ability to provide primary care to affected patients and their families. Management of this condition requires the NP take on the role of gatekeeper, so timely coordination of specialty or subspecialty services is provided. Special consideration should be given to monitoring caregiver fatigue and impact on siblings so family members can be directed to the appropriate support services.
Introduction
Case presentation
In 1981, Drs. Niikawa and Kuroki first described Kabuki Make-up (KMS) or Niikawa Kuroki syndrome independently in Japan. The name “Kabuki make-up” was selected because of the facial resemblance to the makeup of actors in Kabuki, a traditional Japanese theatre form. The term “make-up” was later dropped from the name (Schmiedge, 2009). It is now described as a multiple congenital anomaly mental retardation syndrome characterized by distinguishing facial features. The cause is yet unknown and has an occurrence of 1 in 32,000 births (Schmiedge, 2009). There are slightly more than 400 known cases worldwide and the risk of recurrence for a mother with a KMS child is 50% with each pregnancy (Ng et al., 2010). It is in the best interest of the nurse practitioner (NP) to be familiar with conditions such as this one to be better prepared to care for these patients. The purpose of this article is to examine the pathogenesis, clinical manifestations, diagnosis, and management associated with this rare genetic condition.
B.B. is a 2.5-year-old Hispanic female who was born with KMS (Note: the patient information has been altered to protect the patient’s identity. While the parents did provide consent to publish their story it was felt that altering the patient’s identity was in the patient’s best interest). B.B.’s mother was 24 and her father was 26 at the time of her birth with no indication she was the product of a consanguineous relationship. Nor was there a family history of congenital disorders across the three generations assessed (see Figure 1). B.B.’s mother had no history of smoking or alcohol use and she had no fever episode during her second trimester of pregnancy. She did not receive routine prenatal care because of the lack of health insurance but did have a serum alpha-fetoprotein test in her second trimester. The test result revealed an increased risk for Down syndrome but she declined an amniocentesis. Interestingly, she was also admitted to the hospital during this pregnancy because of episodes of vaginal bleeding and signs of miscarriage.
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Figure 1 Family genogram.
Birth history B.B. was delivered at 37 weeks gestation by repeat cesarean section at a local hospital. A heart murmur was detected at birth along with several dysmorphic features. Her birthweight was 6 pounds and 13 ounces (25th percentile on the growth chart), her birth length was 18.5 inches (10th percentile). Mom did not remember B.B.’s head circumference or APGAR scores. A cardiology referral was made. Her two-dimensional echocardiogram and electrocardiogram (EKG) were within normal limits. She was discharged home with her mother at 4 days of age. Prior to discharge, she received a Hepatitis B vaccine and underwent newborn hearing and metabolic screenings.
also was diagnosed with gastroesophageal reflux disease (GERD) and an esophagogastroduodenoscopy revealed active eosinophilic esophagitis. Her mother reported B.B. had right ear hearing loss secondary to chronic otitis media. The doctors told mom it was because of the “unusual anatomy of B.B.’s ear whereby her ear canals are arched down towards her throat.” In addition to chronic otitis media, she also suffered from frequent bouts of pneumonia. Surgeries performed included repair for bilateral inguinal hernias, an umbilical hernia repair, and exploration of her nasolacrimal ducts. Myringotomy and insertion of tympanostomy tubes were done affording slight relief of her hearing impairment.
Developmental assessment Past medical history Shortly after birth she had a chromosomal study done, which was normal (46, XY). A retroperitoneal ultrasound revealed asymmetric kidneys estimated to be at the upper limit of normal size. At age 3 months, she had one episode of cyanosis with no other symptoms. She was admitted to the hospital and underwent several tests. The working impression was febrile seizure but by the age of two her seizure disorder progressed to seizures without fever. She
Gross motor and fine motor developmental milestones were delayed for age and she was not interested in potty training. At 25 months of age, she had less than 30 words in her vocabulary and was able to sign less than five words. She was unable to remove any of her clothing or assist with dressing. She did not recognize any of her body parts. B.B. was able to make great eye contact with the examiner and smiled several times. She was also able to follow simple commands, responded to her name but 523
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Table 1 Selected normal developmental milestones and B.B.’s development Normal development Social-emotional development Imitates parents and playmates (24 months) Able to take off some clothing items (18 months) Language/cognitive development Has at least 50 (24 months) Puts together two to three words (24 months) Points to objects to indicate wants (12 months) Recognizes name (12 months) Knows several body parts (18 months) Follows simple comments (18 months) Gross motor development Walks alone, stands on tip toes (24 months) Climbs furniture (24 months), runs
did not spontaneously speak any words. B.B. did not point to items of interest but tried to get them independently. During the interview, she appeared to be absence of fear. Her mother reported B.B. often rocked herself and had some imitative behavior. She also liked to do head banging and sit in the closet. She was not able to sleep very long at night and had difficulty initiating sleep (see Table 1).
B.B.’s development at 30 months Social development Some imitative behavior Not able to take off or assist with taking off clothing Language development Repeats less than 30 word but does not speak Does not spontaneously speak words Does not point to indicate wants Recognizes name but does not state name Does not know body parts Follows simple comments Gross motor development Walks without help, stands on tip toes Climbs furniture, runs
morphic features consistent with KMS. Using this variant filtration strategy, Ng et al. (2010) found 73% had truncated defects, 25 were confirmed de novo mutations and only two cases demonstrated a familial association. This sporadically occurring syndrome suggests heterozygous de novo variants may be the cause.
Clinical manifestations Physical exam Physical exam findings were noncontributory except for microcephaly (3rd percentile), and course facial features consistent with KMS such as long palpebral fissures with upslanting of the lateral palpebral folds. She had mild ptosis of the right eye and thick eyelashes. Her ears were posteriorly rotated, and she had a high arched palate. Neurologically, there was global developmental delay (as stated above). B.B. had brachydactyly and deep palmar flexion creases to both hands. She also had deep creases on the plantar surfaces of both feet and prominent toe pads.
Pathogenesis, clinical manifestations, and diagnosis KMS is a disorder that is very uncommon. The proportion of male to female occurrence is equal and no correlation with birth order has been found (Ng et al., 2010). It is suggested each patient with KMS has a new mutation (Ng et al., 2010) in an autosomal dominant Mendelian fashion. For the great majority of children, chromosomal linkage studies yield normal results (Ng et al., 2010; Schmiedge, 2009) because of the inability to detect microscopic deletions or duplications (Schmiedge, 2009). Recently, Ng et al. (2010) were able to identify the causal variants in the MLL2 on chromosome 12 using the Exome sequencing technique on 102 children with dys524
The children are of normal size at birth but have postnatal growth deficiency whereby 80% eventually have short stature. Clinical recognition of the syndrome in the neonate is difficult as the phenotype appears to evolve with time in early childhood. The diagnosis is, on average, made by the age of 2 years (Lung & Rennie, 2006). While there is no specific diagnostic criteria, children with KMS have distinct facial features that can include arched eyebrows, thick eyelashes, eversion of the lateral lower lid, depressed nasal tip, prominent ears, and long palpebral fissures which all contribute to the resemblance of a Kabuki actor, especially in children of Asian descent (Schmiedge, 2009). A cleft or high arched palate has been observed in 80% of patients (Schmiedge, 2009). Less frequent craniofacial abnormalities can include epicanthal folds, ptosis, strabismus, micrognathia, abnormal or absent teeth, widely spaced teeth, and a low posterior hairline. The ears are large and prominent in 85% of individuals with this syndrome and some display ear malformations (Schmiedge, 2009). Other dysmorphic features include skeletal abnormalities. The most common is a short incurved fifth finger (Schmiedge, 2009) and prominent fingertip pads (Upton, Stadler, Landis, & Wulfsberg, 2003). Vertebral anomalies can include butterfly vertebra, sagittal cleft, narrow intervertebral disc space, spina bifida occulta, and scoliosis (Schmiedge, 2009).
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Congenital heart disease occurs in 30%–50% of individuals (Schmiedge, 2009). The most common heart defects are ventricular septal defect, atrial septal defect, and bicuspid aortic valves (Schmeidge, 2009). Other abnormalities include undescended testes in males, urinary tract malformations, and kidney anomalies. Most individuals with KMS have mild-to-moderate intellectual disability. The mean IQ of children with KMS is 62, which is consistent with mild retardation. Expressive language is delayed and visual-spatial abilities are impaired. Math skills tend to be a relative strength (Adam & Hudgins, 2005). Autism spectrum disorder has been reported in approximately 16% of patients (Adam & Hudgins, 2004). Delay in speech and language acquisition is very common, exacerbated by craniofacial anomalies, hypotonia, and poor coordination. Sensory issues include need for oral stimulation, tactile defensiveness toward various sensations and stimuli, panic-like reactions to certain noises, and aversion to textures and or smells of select foods. Individuals with KMS have a need for routine. They have a tendency to fixate on certain activities or thoughts. It appears they have excellent memories for face recognition, song lyrics, and dates of events. Anxiety, obsessive/compulsive traits, and autistic-type behaviors are commonly observed (Schmiedge, 2009). Medical complications reported in KMS include poor feeding in infancy; recurrent otitis media in 50%, hearing loss in 24%, early breast development in 25% of females, obesity with onset at puberty in 20%, and seizures in 15% (Schmiedge, 2009). IgA and IgG may be decreased, and autoimmune diseases, such as idiopathic thrombocytopenia, occur more frequently. Endocrine problems reported in some patients include diabetes, hypothyroidism, growth hormone deficiency, and precocious puberty. The adults with KMS are shorter than the norm, two or more standard deviations below the mean (Schmiedge, 2009). Loose ligaments and hypotonia may cause joint or patella dislocations especially if obesity becomes an issue in teen or adult years (Schmiedge, 2009). Hemolytic anemia and hypogammaglobulimenia have also been reported (Schmiedge, 2009). Not being a progressive disease, the prognosis for survival into adulthood is relatively good as KMS is not typically associated with severe medical complications (Lung & Rennie, 2006; Schmiedge, 2009) even with multiple organ system involvement. This is also true for those with more involved congenital anomalies, such as congenital heart defects and infections if their conditions are well managed (Adam & Hudgins, 2004). There is too wide a range of abilities to make a general prediction as to the future of these patients as they reach adulthood. The ability to live independently is dependent on individual capabilities and support systems. A 2004 study that
included long-term follow-up of three individuals with KMS, found they were able to achieve independent daily living skills and were able to hold part-time jobs but all needed to live in sheltered environments. This indicates appropriate long-term planning is needed in spite of the limited amount of evidence currently available on adult patients with KMS (Schmiedge, 2009).
Management Making the diagnosis The management of patients with KMS is variable and dependent on the constellation of diseases that may or may not be present at birth. In subtle disease, the child may be seen for normal childhood well care until s/he is around 2–2.5 years old when facial features associated with this syndrome become more evident. Indications that should raise the index of suspicion for KMS during wellness assessments include: (a) short statute for age based on the gender appropriate growth chart, (b) the presences of hypotonia and poor sucking, or (c) developmental delays when performing the Denver II screening test. On the other hand, a newborn with at least three midline anomalies (e.g., cleft palate/lip, hearing defect, unusual facial features, congenital heart murmur, etc.) should be referred to both a geneticist to identify the underlying congenital/genetic condition and specialists for the systems affected. In B.B.’s case, early genetic referral was made because of her presenting phenotype along with several midline anomalies. She was also referred to specialist to assess affected systems. A kidney assessment might not ordinarily be part of the routine work-up for KMS, but in B.B.’s case one was performed because of the posterior rotation of her ears. In general, when infants present with ear(s) mal-placement/deformity or pitting in the prearicular area, they run the risk of also having kidney anomalies.
Considerations for caring for a child with KMS Ongoing management of existing conditions is imperative to minimize susceptibility to infection, dental issues, or cardiac problems. Also, virulence is necessary because some conditions may appear for the first time when these patients become older (Schmiedge, 2009). For example, seizures may not manifest itself until older childhood or loose ligaments and hypotonia may cause joint or patella dislocations in teen or adult years. Hemolytic anemia, hypogammaglobulinemia, and low IgA levels can also be present. However, the frequency and severity of the immune deficiency has not been clearly 525
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defined, but evidence suggests hypogammaglobulinemia is the most frequent finding in KMS children (Hoffmann et al., 2005). Usually the pattern of antibody abnormalities observed in KMS children resembles common variable immune deficiency rendering them to be prone to infections. Because of this increased susceptibility, children with KMS should have immunologic evaluation when diagnosed with KMS to reduce preventable morbidity and mortality. Because of the potential complexity of care, the primary care NPs managing KMS patients assumes multiple roles, one being the overall coordinator of care. This includes primarily health promotion of children with genetic conditions. The NP can help reduce morbidity by assisting parents to use specialized services, teaching health principles, monitoring and evaluating patients, and working to alleviate the stress of family caregivers (Burns, Dunn, Brady, Star, & Blosser, 2009). Specifically, the NP can implement several interventions for health promotion such as the instruction of basic hand hygiene to all family members to prevent spread of infection, providing education on the importance of yearly influenza vaccination, monitoring of daily caloric intake, and 24-h dietary recall at each office visit to assess risk for obesity and providing anticipatory guidance for growth and development. The American Academy of Pediatrics (AAP) recommends monitoring children’s developmental progress as part of preventive health care (AAP, 2003). Early identification of developmental problems with early intervention is an important factor in caring for children with disabilities and chronic conditions (Nickel & Desch, 2010). Detection of developmental delays warrants referral to speech therapy, occupational therapy, and physical therapy. Other services include pediatric dental assessments and referral to behavioral pediatrics for behavior modification strategies for autistic-like mannerisms. Pharmacological treatment would depend on the comorbidities present. B.B. was maintained on levetiracetam (Keppra), an antiepileptic medication for her seizure disorder. Because of recurrent bouts of infections such as pneumonia and otitis media, she was given several antibiotics ranging from amoxicillin to several cephalosporins. She was also maintained on an H2-receptor antagonist for her GERD and eosinophilic esophagitis. Finally, providing families with resources helps to provide a safety net. Some available resources are the National Information Center for Children and Youth with
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Disabilities; National Organization for Rare Disorders, Inc.; and the Federation for Children with Special Needs. Another potential agency is the Sibling Support Project. This is a national effort dedicated to the life-long concerns of brothers and sisters of people who have special health, developmental, or mental health concerns. It is based in Seattle and has trained service providers in all 50 states, England, Ireland, New Zealand, and Japan. The Kabuki Syndrome network is another resource that can benefit families with KMS.
Summary Children with chronic conditions such as KMS, like their normal peers, will seek primary healthcare services. These services include assurance of ambulatory and inpatient care, provision of care over an extended period of time, identification and referral to subspecialists, and interaction with school and community agencies. Maintenance of pertinent medical information through the use of a centralized recordkeeping database can track these activities to optimize health care of KMS patients (Nickel & Desch, 2010). Being knowledgeable about this rare genetic disorder, the NP can be a valuable partner of the interdisciplinary team caring for these children. The complexity of rare genetic conditions such as KMS presents many challenges in diagnosis and management but should not deter the NP from accepting care of these patients.
References Adam, M. P., & Hudgins, L. (2005). Kabuki Syndrome: A review. Clinical Genetics, 67(3), 209–219. American Academy of Pediatrics (AAP). (2003). Family-centered care and the pediatrician’s role. Pediatrics, 112, 691–696. Burns, C. E., Dunn, A. M., Brady, M. A., Starr, N. B., & Blosser, C. G. (2009). Pediatric primary care (4th ed.). St. Louis, MO: Saunders Elsevier. Hoffman, J. D., Ciprero, K. L., Sullivan, K. E., Kaplan, P. B., McDonald-McGinn, D. M, Zackai, E. H., & Hing, J. E. (2005). Immune abnormalities are a frequent manifestation of Kabuki Syndrome. American Journal of Medical Genetics, 135, 278–281. Lung, Z. H. S., & Rennie, A. (2006). Kabuki Syndrome: A case report. Journal of Orthodontics, 3(4), 242–245. Ng, S. B., Buckingham, K. J., Lee, C., Bigham, A. W., Tabor, H. K., Dent, K. M, . . . Shendure, J. (2010). Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Natural Genetics, 42, 790–793. Nickel, R. E., & Desch, L. W. (2000). The physician’s guide to caring for children with disabilities and chronic conditions. Baltimore: Paul H. Brookes Publishing. Schmiedge, M. (2009). Facts about Kabuki. Retrieved from www.kabukisyndrome.com Upton, S., Stadler, C. S., Landis, P., & Wulfsberg, E. A. (2003). Speech characteristics in Kabuki Syndrome. American Journal of Medical Genetics, 166A(4), 338–341.
Kabuki syndrome: A challenge for the primary care provider Bonnie Crane, MSN, PNP (Pediatric Clinical Education Coordinator)1 , Patricia T. Alpert, DrPH, MSN, FNP-BC, PNP-BC, CNE, FAANP (Associate Professor & Chair of the Physiologic Department)2 , Dianne Cyrkiel, MSN, PNP-C (Instructor)2 , & Alan Jauregui, MD, MSN, FNP (Instructor)2 1 2
Sunrise Children’s Hospital, Las Vegas, Nevada School of Nursing, University of Nevada, Las Vegas, Nevada
Keywords Developmental delay; genetics; primary care; syndromes. Correspondence Patricia T. Alpert, DrPH, MSN, FNP-BC, PNP-BC, CNE, FAANP, Associate Professor & Chair of the Physiologic Department, School of Nursing, University of Nevada, Las Vegas, 4505 Maryland Parkway, Box 453018, Las Vegas, NV 89154-3018. Tel: 702-895-3810; Fax: 702-895-4807; E-mail: [email protected] Received: August 2011; accepted: January 2012 doi: 10.1002/2327-6924.12044
Abstract Purpose: Using a case format, the pathogenesis, clinical manifestations, diagnosis, and management of Kabuki syndrome, a rare genetic condition, is presented. Nurse practitioners (NPs) may encounter patients presenting to the primary care setting with this rare syndrome; understanding this condition may help them to better care for these patients. Data source: A case presentation of a pediatric patient supported by the currently available literature from multiple health and medial databases. Conclusion: Kabuki syndrome is a rare phenomenon that occurs in 1 in every 32,000 births. A diagnosis of this syndrome may take several months to years because there are no specific tests, and the physical features may be subtle at birth, becoming more pronounced over a period of time during childhood. The degree of disease severity varies widely. Implications for practice: Understanding this syndrome increases the NP’s ability to provide primary care to affected patients and their families. Management of this condition requires the NP take on the role of gatekeeper, so timely coordination of specialty or subspecialty services is provided. Special consideration should be given to monitoring caregiver fatigue and impact on siblings so family members can be directed to the appropriate support services.
Introduction
Case presentation
In 1981, Drs. Niikawa and Kuroki first described Kabuki Make-up (KMS) or Niikawa Kuroki syndrome independently in Japan. The name “Kabuki make-up” was selected because of the facial resemblance to the makeup of actors in Kabuki, a traditional Japanese theatre form. The term “make-up” was later dropped from the name (Schmiedge, 2009). It is now described as a multiple congenital anomaly mental retardation syndrome characterized by distinguishing facial features. The cause is yet unknown and has an occurrence of 1 in 32,000 births (Schmiedge, 2009). There are slightly more than 400 known cases worldwide and the risk of recurrence for a mother with a KMS child is 50% with each pregnancy (Ng et al., 2010). It is in the best interest of the nurse practitioner (NP) to be familiar with conditions such as this one to be better prepared to care for these patients. The purpose of this article is to examine the pathogenesis, clinical manifestations, diagnosis, and management associated with this rare genetic condition.
B.B. is a 2.5-year-old Hispanic female who was born with KMS (Note: the patient information has been altered to protect the patient’s identity. While the parents did provide consent to publish their story it was felt that altering the patient’s identity was in the patient’s best interest). B.B.’s mother was 24 and her father was 26 at the time of her birth with no indication she was the product of a consanguineous relationship. Nor was there a family history of congenital disorders across the three generations assessed (see Figure 1). B.B.’s mother had no history of smoking or alcohol use and she had no fever episode during her second trimester of pregnancy. She did not receive routine prenatal care because of the lack of health insurance but did have a serum alpha-fetoprotein test in her second trimester. The test result revealed an increased risk for Down syndrome but she declined an amniocentesis. Interestingly, she was also admitted to the hospital during this pregnancy because of episodes of vaginal bleeding and signs of miscarriage.
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Figure 1 Family genogram.
Birth history B.B. was delivered at 37 weeks gestation by repeat cesarean section at a local hospital. A heart murmur was detected at birth along with several dysmorphic features. Her birthweight was 6 pounds and 13 ounces (25th percentile on the growth chart), her birth length was 18.5 inches (10th percentile). Mom did not remember B.B.’s head circumference or APGAR scores. A cardiology referral was made. Her two-dimensional echocardiogram and electrocardiogram (EKG) were within normal limits. She was discharged home with her mother at 4 days of age. Prior to discharge, she received a Hepatitis B vaccine and underwent newborn hearing and metabolic screenings.
also was diagnosed with gastroesophageal reflux disease (GERD) and an esophagogastroduodenoscopy revealed active eosinophilic esophagitis. Her mother reported B.B. had right ear hearing loss secondary to chronic otitis media. The doctors told mom it was because of the “unusual anatomy of B.B.’s ear whereby her ear canals are arched down towards her throat.” In addition to chronic otitis media, she also suffered from frequent bouts of pneumonia. Surgeries performed included repair for bilateral inguinal hernias, an umbilical hernia repair, and exploration of her nasolacrimal ducts. Myringotomy and insertion of tympanostomy tubes were done affording slight relief of her hearing impairment.
Developmental assessment Past medical history Shortly after birth she had a chromosomal study done, which was normal (46, XY). A retroperitoneal ultrasound revealed asymmetric kidneys estimated to be at the upper limit of normal size. At age 3 months, she had one episode of cyanosis with no other symptoms. She was admitted to the hospital and underwent several tests. The working impression was febrile seizure but by the age of two her seizure disorder progressed to seizures without fever. She
Gross motor and fine motor developmental milestones were delayed for age and she was not interested in potty training. At 25 months of age, she had less than 30 words in her vocabulary and was able to sign less than five words. She was unable to remove any of her clothing or assist with dressing. She did not recognize any of her body parts. B.B. was able to make great eye contact with the examiner and smiled several times. She was also able to follow simple commands, responded to her name but 523
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Table 1 Selected normal developmental milestones and B.B.’s development Normal development Social-emotional development Imitates parents and playmates (24 months) Able to take off some clothing items (18 months) Language/cognitive development Has at least 50 (24 months) Puts together two to three words (24 months) Points to objects to indicate wants (12 months) Recognizes name (12 months) Knows several body parts (18 months) Follows simple comments (18 months) Gross motor development Walks alone, stands on tip toes (24 months) Climbs furniture (24 months), runs
did not spontaneously speak any words. B.B. did not point to items of interest but tried to get them independently. During the interview, she appeared to be absence of fear. Her mother reported B.B. often rocked herself and had some imitative behavior. She also liked to do head banging and sit in the closet. She was not able to sleep very long at night and had difficulty initiating sleep (see Table 1).
B.B.’s development at 30 months Social development Some imitative behavior Not able to take off or assist with taking off clothing Language development Repeats less than 30 word but does not speak Does not spontaneously speak words Does not point to indicate wants Recognizes name but does not state name Does not know body parts Follows simple comments Gross motor development Walks without help, stands on tip toes Climbs furniture, runs
morphic features consistent with KMS. Using this variant filtration strategy, Ng et al. (2010) found 73% had truncated defects, 25 were confirmed de novo mutations and only two cases demonstrated a familial association. This sporadically occurring syndrome suggests heterozygous de novo variants may be the cause.
Clinical manifestations Physical exam Physical exam findings were noncontributory except for microcephaly (3rd percentile), and course facial features consistent with KMS such as long palpebral fissures with upslanting of the lateral palpebral folds. She had mild ptosis of the right eye and thick eyelashes. Her ears were posteriorly rotated, and she had a high arched palate. Neurologically, there was global developmental delay (as stated above). B.B. had brachydactyly and deep palmar flexion creases to both hands. She also had deep creases on the plantar surfaces of both feet and prominent toe pads.
Pathogenesis, clinical manifestations, and diagnosis KMS is a disorder that is very uncommon. The proportion of male to female occurrence is equal and no correlation with birth order has been found (Ng et al., 2010). It is suggested each patient with KMS has a new mutation (Ng et al., 2010) in an autosomal dominant Mendelian fashion. For the great majority of children, chromosomal linkage studies yield normal results (Ng et al., 2010; Schmiedge, 2009) because of the inability to detect microscopic deletions or duplications (Schmiedge, 2009). Recently, Ng et al. (2010) were able to identify the causal variants in the MLL2 on chromosome 12 using the Exome sequencing technique on 102 children with dys524
The children are of normal size at birth but have postnatal growth deficiency whereby 80% eventually have short stature. Clinical recognition of the syndrome in the neonate is difficult as the phenotype appears to evolve with time in early childhood. The diagnosis is, on average, made by the age of 2 years (Lung & Rennie, 2006). While there is no specific diagnostic criteria, children with KMS have distinct facial features that can include arched eyebrows, thick eyelashes, eversion of the lateral lower lid, depressed nasal tip, prominent ears, and long palpebral fissures which all contribute to the resemblance of a Kabuki actor, especially in children of Asian descent (Schmiedge, 2009). A cleft or high arched palate has been observed in 80% of patients (Schmiedge, 2009). Less frequent craniofacial abnormalities can include epicanthal folds, ptosis, strabismus, micrognathia, abnormal or absent teeth, widely spaced teeth, and a low posterior hairline. The ears are large and prominent in 85% of individuals with this syndrome and some display ear malformations (Schmiedge, 2009). Other dysmorphic features include skeletal abnormalities. The most common is a short incurved fifth finger (Schmiedge, 2009) and prominent fingertip pads (Upton, Stadler, Landis, & Wulfsberg, 2003). Vertebral anomalies can include butterfly vertebra, sagittal cleft, narrow intervertebral disc space, spina bifida occulta, and scoliosis (Schmiedge, 2009).
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Congenital heart disease occurs in 30%–50% of individuals (Schmiedge, 2009). The most common heart defects are ventricular septal defect, atrial septal defect, and bicuspid aortic valves (Schmeidge, 2009). Other abnormalities include undescended testes in males, urinary tract malformations, and kidney anomalies. Most individuals with KMS have mild-to-moderate intellectual disability. The mean IQ of children with KMS is 62, which is consistent with mild retardation. Expressive language is delayed and visual-spatial abilities are impaired. Math skills tend to be a relative strength (Adam & Hudgins, 2005). Autism spectrum disorder has been reported in approximately 16% of patients (Adam & Hudgins, 2004). Delay in speech and language acquisition is very common, exacerbated by craniofacial anomalies, hypotonia, and poor coordination. Sensory issues include need for oral stimulation, tactile defensiveness toward various sensations and stimuli, panic-like reactions to certain noises, and aversion to textures and or smells of select foods. Individuals with KMS have a need for routine. They have a tendency to fixate on certain activities or thoughts. It appears they have excellent memories for face recognition, song lyrics, and dates of events. Anxiety, obsessive/compulsive traits, and autistic-type behaviors are commonly observed (Schmiedge, 2009). Medical complications reported in KMS include poor feeding in infancy; recurrent otitis media in 50%, hearing loss in 24%, early breast development in 25% of females, obesity with onset at puberty in 20%, and seizures in 15% (Schmiedge, 2009). IgA and IgG may be decreased, and autoimmune diseases, such as idiopathic thrombocytopenia, occur more frequently. Endocrine problems reported in some patients include diabetes, hypothyroidism, growth hormone deficiency, and precocious puberty. The adults with KMS are shorter than the norm, two or more standard deviations below the mean (Schmiedge, 2009). Loose ligaments and hypotonia may cause joint or patella dislocations especially if obesity becomes an issue in teen or adult years (Schmiedge, 2009). Hemolytic anemia and hypogammaglobulimenia have also been reported (Schmiedge, 2009). Not being a progressive disease, the prognosis for survival into adulthood is relatively good as KMS is not typically associated with severe medical complications (Lung & Rennie, 2006; Schmiedge, 2009) even with multiple organ system involvement. This is also true for those with more involved congenital anomalies, such as congenital heart defects and infections if their conditions are well managed (Adam & Hudgins, 2004). There is too wide a range of abilities to make a general prediction as to the future of these patients as they reach adulthood. The ability to live independently is dependent on individual capabilities and support systems. A 2004 study that
included long-term follow-up of three individuals with KMS, found they were able to achieve independent daily living skills and were able to hold part-time jobs but all needed to live in sheltered environments. This indicates appropriate long-term planning is needed in spite of the limited amount of evidence currently available on adult patients with KMS (Schmiedge, 2009).
Management Making the diagnosis The management of patients with KMS is variable and dependent on the constellation of diseases that may or may not be present at birth. In subtle disease, the child may be seen for normal childhood well care until s/he is around 2–2.5 years old when facial features associated with this syndrome become more evident. Indications that should raise the index of suspicion for KMS during wellness assessments include: (a) short statute for age based on the gender appropriate growth chart, (b) the presences of hypotonia and poor sucking, or (c) developmental delays when performing the Denver II screening test. On the other hand, a newborn with at least three midline anomalies (e.g., cleft palate/lip, hearing defect, unusual facial features, congenital heart murmur, etc.) should be referred to both a geneticist to identify the underlying congenital/genetic condition and specialists for the systems affected. In B.B.’s case, early genetic referral was made because of her presenting phenotype along with several midline anomalies. She was also referred to specialist to assess affected systems. A kidney assessment might not ordinarily be part of the routine work-up for KMS, but in B.B.’s case one was performed because of the posterior rotation of her ears. In general, when infants present with ear(s) mal-placement/deformity or pitting in the prearicular area, they run the risk of also having kidney anomalies.
Considerations for caring for a child with KMS Ongoing management of existing conditions is imperative to minimize susceptibility to infection, dental issues, or cardiac problems. Also, virulence is necessary because some conditions may appear for the first time when these patients become older (Schmiedge, 2009). For example, seizures may not manifest itself until older childhood or loose ligaments and hypotonia may cause joint or patella dislocations in teen or adult years. Hemolytic anemia, hypogammaglobulinemia, and low IgA levels can also be present. However, the frequency and severity of the immune deficiency has not been clearly 525
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defined, but evidence suggests hypogammaglobulinemia is the most frequent finding in KMS children (Hoffmann et al., 2005). Usually the pattern of antibody abnormalities observed in KMS children resembles common variable immune deficiency rendering them to be prone to infections. Because of this increased susceptibility, children with KMS should have immunologic evaluation when diagnosed with KMS to reduce preventable morbidity and mortality. Because of the potential complexity of care, the primary care NPs managing KMS patients assumes multiple roles, one being the overall coordinator of care. This includes primarily health promotion of children with genetic conditions. The NP can help reduce morbidity by assisting parents to use specialized services, teaching health principles, monitoring and evaluating patients, and working to alleviate the stress of family caregivers (Burns, Dunn, Brady, Star, & Blosser, 2009). Specifically, the NP can implement several interventions for health promotion such as the instruction of basic hand hygiene to all family members to prevent spread of infection, providing education on the importance of yearly influenza vaccination, monitoring of daily caloric intake, and 24-h dietary recall at each office visit to assess risk for obesity and providing anticipatory guidance for growth and development. The American Academy of Pediatrics (AAP) recommends monitoring children’s developmental progress as part of preventive health care (AAP, 2003). Early identification of developmental problems with early intervention is an important factor in caring for children with disabilities and chronic conditions (Nickel & Desch, 2010). Detection of developmental delays warrants referral to speech therapy, occupational therapy, and physical therapy. Other services include pediatric dental assessments and referral to behavioral pediatrics for behavior modification strategies for autistic-like mannerisms. Pharmacological treatment would depend on the comorbidities present. B.B. was maintained on levetiracetam (Keppra), an antiepileptic medication for her seizure disorder. Because of recurrent bouts of infections such as pneumonia and otitis media, she was given several antibiotics ranging from amoxicillin to several cephalosporins. She was also maintained on an H2-receptor antagonist for her GERD and eosinophilic esophagitis. Finally, providing families with resources helps to provide a safety net. Some available resources are the National Information Center for Children and Youth with
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Disabilities; National Organization for Rare Disorders, Inc.; and the Federation for Children with Special Needs. Another potential agency is the Sibling Support Project. This is a national effort dedicated to the life-long concerns of brothers and sisters of people who have special health, developmental, or mental health concerns. It is based in Seattle and has trained service providers in all 50 states, England, Ireland, New Zealand, and Japan. The Kabuki Syndrome network is another resource that can benefit families with KMS.
Summary Children with chronic conditions such as KMS, like their normal peers, will seek primary healthcare services. These services include assurance of ambulatory and inpatient care, provision of care over an extended period of time, identification and referral to subspecialists, and interaction with school and community agencies. Maintenance of pertinent medical information through the use of a centralized recordkeeping database can track these activities to optimize health care of KMS patients (Nickel & Desch, 2010). Being knowledgeable about this rare genetic disorder, the NP can be a valuable partner of the interdisciplinary team caring for these children. The complexity of rare genetic conditions such as KMS presents many challenges in diagnosis and management but should not deter the NP from accepting care of these patients.
References Adam, M. P., & Hudgins, L. (2005). Kabuki Syndrome: A review. Clinical Genetics, 67(3), 209–219. American Academy of Pediatrics (AAP). (2003). Family-centered care and the pediatrician’s role. Pediatrics, 112, 691–696. Burns, C. E., Dunn, A. M., Brady, M. A., Starr, N. B., & Blosser, C. G. (2009). Pediatric primary care (4th ed.). St. Louis, MO: Saunders Elsevier. Hoffman, J. D., Ciprero, K. L., Sullivan, K. E., Kaplan, P. B., McDonald-McGinn, D. M, Zackai, E. H., & Hing, J. E. (2005). Immune abnormalities are a frequent manifestation of Kabuki Syndrome. American Journal of Medical Genetics, 135, 278–281. Lung, Z. H. S., & Rennie, A. (2006). Kabuki Syndrome: A case report. Journal of Orthodontics, 3(4), 242–245. Ng, S. B., Buckingham, K. J., Lee, C., Bigham, A. W., Tabor, H. K., Dent, K. M, . . . Shendure, J. (2010). Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Natural Genetics, 42, 790–793. Nickel, R. E., & Desch, L. W. (2000). The physician’s guide to caring for children with disabilities and chronic conditions. Baltimore: Paul H. Brookes Publishing. Schmiedge, M. (2009). Facts about Kabuki. Retrieved from www.kabukisyndrome.com Upton, S., Stadler, C. S., Landis, P., & Wulfsberg, E. A. (2003). Speech characteristics in Kabuki Syndrome. American Journal of Medical Genetics, 166A(4), 338–341.
